Practical access to metallo thiophenes: Regioselective synthesis of 2,4-disubstituted thiophenes

Article abstract of DOI:10.1021/op100226k

This report describes a protocol for functionalization of thiophenes, utilizing a regioselective magnesiation mediated by commercial Grignard reagents and catalytic 2,2,6,6-tetramethylpiperidine. This metalation provides practical access to metallo thiophenes, avoiding cryogenic conditions, prolonged reaction times, and prohibitively expensive reagents. Application to a target thiophene-phthalazinone 6 was accomplished by addition of 2-magnesio-4- methylthiophene to phthalic anhydride, providing the product with >40:1 regioselectivity. This also solved a chemoselectivity issue encountered with analogous lithio-thiophene reagents and cyclic anhydrides, or with magnesio-thiophene generated by simultaneous lithium-to-magnesium transmetalation/anhydride acylation. These alternative in situ transmetalation sequences were plagued by an age effect dictated by the kinetic solubility of MgCl₂/THF complexes.

Full text of DOI:10.1021/op100226k

Organic Process Research & Development 2010, 14, 1427–1431
Practical Access to Metallo Thiophenes: Regioselective Synthesis of
2,4-Disubstituted Thiophenes
Sylvie M. Asselin,*,† Matthew M. Bio, Neil F. Langille,* and Ka Yi Ngai
Chemical Process R&D, Amgen, Inc., 360 Binney Street, Building 1000, Cambridge, Massachusetts 02142, United States
Abstract:
Li-Based Deprotonation. The deprotonation of 3-meth-
ylthiophene has been the subject of previous research studies.4
Smith and co-workers reported excellent regioselectivity in the
deprotonation of 3-methylthiophene (>35:1) using n-BuLi and
2,2,6,6-tetramethylpiperidine (TMP-H).4c However, the reported
regioselectivity could only be achieved at -78 °C. A practical,
although under-utilized, lithium amide formation involves
dropwise addition of an alkyllithium to a substoichiometric
amount of amine in the presence of the acidic reactant.5
Application of this method to 3-methylthiophene produced the
desired lithio-thiophene 2a (Scheme 2) with useful levels of
thiophene regioselectivity (12:1)6 using 10 mol % TMP-H at
-20 °C.
However, direct addition of lithio-thiophene 2a to phthalic
anhydride 3 gave a 1:2 mixture of desired keto acid 4 and
undesired bis-thiophene 5.7 Alternatively transmetalation of
lithio-thiophene 2a with MgCl2 produced magnesio-thiophene
2b, which reacted with 3 to produce the desired product 4 in
88% assay yield with >30:1 chemoselectivity (4/5). The
deprotonation/transmetalation/acylation sequence provided keto
acid 4 via preformed Mg-thiophene 2b; however this procedure
represented a tedious three-vessel operation.
This report describes a protocol for functionalization of thiophenes,
utilizing a regioselective magnesiation mediated by commercial
Grignard reagents and catalytic 2,2,6,6-tetramethylpiperidine. This
metalation provides practical access to metallo thiophenes, avoiding
cryogenic conditions, prolonged reaction times, and prohibitively
expensive reagents. Application to a target thiophene-phthalazi-
none 6 was accomplished by addition of 2-magnesio-4-methyl-
thiophene to phthalic anhydride, providing the product with >40:1
regioselectivity. This also solved a chemoselectivity issue encoun-
tered with analogous lithio-thiophene reagents and cyclic anhy-
drides, or with magnesio-thiophene generated by simultaneous
lithium-to-magnesium transmetalation/anhydride acylation. These
alternative in situ transmetalation sequences were plagued by an
age effect dictated by the kinetic solubility of MgCl2/THF complexes.
Introduction
A recent project required a practical synthetic preparation
of thiophene-phthalazinone 6.1,2 A logical precursor to this
molecule is keto acid 4, formed through union of 3-methyl-
thiophene 1 and phthalic anhydride 3 (Scheme 1). Upon
subjection of 1 and 3 to Friedel-Crafts conditions3 (AlCl3,
CH2Cl2, -10 °C), the more electron-rich alkene reacted
selectively to form the undesired 2,3-keto acid regioisomer 4′
(8:1 ratio, 4′:4). Therefore, preformed 2-metallo-4-methylth-
iophene 2 was explored as a nucleophile to form keto acid 4,
where steric factors could promote the desired 2,4-regioisomer.
A successful sequence would require practical, scalable condi-
tions to address regioselective deprotonation to form a 2,4-
thiophene isomer (2 vs 2′) and subsequent chemoselective
monoaddition to the anhydride (4 vs 5) to provide this key
intermediate.
If Li-to-Mg transmetalation (2a to 2b) occurred faster than
addition of 2a to phthalic anhydride, Mg-thiophene 2b could
potentially be generated in situ in the presence of the electro-
phile, accomplishing two steps of the process simultaneously
in a single vessel. Slow addition of Li-thiophene 2a could be
utilized to exploit this rate difference. If this proposed sequence
were successful, the resulting Mg-thiophene 2b would react to
form the stabilized Mg-alkoxide 7b, chemoselectively producing
the desired keto acid 4. To test this hypothesis, Li-thiophene
2a was generated via the catalytic TMP-H method and added
dropwise to a phthalic anhydride/MgCl2/THF mixture at -20
°C, producing the desired keto acid 4 in 80% assay yield, with
a 10:1 ratio of mono- to bis-thiophene products (Table 1, entry
1). In preparation for scaling, slurries of phthalic anhydride/
MgCl2/THF were aged at 20 °C prior to introduction of Li-
thiophene 2a. This age time had a dramatic effect: when phthalic
* Authorstowhomcorrespondencemaybesent.E-mail:sylvie.asselin@amgen.com;
neil.langille@amgen.com.
(4) (a) Ramanathan, V.; Levine, R. J. Org. Chem. 1962, 27, 1667–1670.
(b) Gronowitz, S.; Cederlund, B.; Hornfeldt, A.-B. Chem. Scr. 1974,
5, 217–226. (c) Smith, K.; Barrat, M. L. J. Org. Chem. 2007, 72,
1031–1034.
† Current address: Chemical Process R&D, Amgen, Inc., One Amgen Center
Drive, Thousand Oaks, California 91320, United States
(1) Cee, V. J.; Deak, H. L.; Du, B.; Geuns-Meyer, S. D.; Hodous, B. L.;
Nguyen, H. N.; Olivieri, P. R.; Patel, V. F.; Romero, K.; Schenkel, L.
Chem. Abstr. 2007, 147, 235186. Preparation of Substituted Phthalazin-
amines as Aurora Kinase Modulators. PCT Int. Appl. WO/2007/
087276, 2007.
(5) (a) Alorati, A. D.; Bio, M. M.; Brands, K. M. J.; Cleator, E.; Davies,
A. J.; Wilson, R. D.; Wise, C. S. Org. Process Res. DeV. 2007, 11,
637–641. (b) Klingensmith, L. M.; Bio, M. M.; Moniz, G. A.
Tetrahedron Lett. 2007, 48, 8242–8245.
(2) For alternate synthesis, see: (a) Iwase, N.; Morinaka, Y.; Tamao, Y.;
Kanayama, T.; Yamada, K. Chem. Abstr. 1993, 119, 249963. 3,6-
Disubstituted Pyridazine Derivative Blood Platelet Aggregation Inhibi-
tors. Eur. Pat. Appl. EP 534443 19920924, 1993.
(6) Regioisomeric ratio upon reaction with phthalic anhydride (not a direct
measurement of deprotonation).
(7) Analysis by 13C NMR indicates that isolated keto acid 4 exists as the
open form shown in Scheme 2 and side product 5 exists as the closed
lactone form.
(3) Weinmayr, V. J. Am. Chem. Soc. 1952, 74, 4353–4357.
10.1021/op100226k  2010 American Chemical Society
Published on Web 10/13/2010
Vol. 14, No. 6, 2010 / Organic Process Research & Development
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Scheme 1. Plausible synthetic routes to phthalazinone 6
Table 1. Transmetalation dynamics and effect on acylation
entry
age timea
yield of 4b (%)
(4:5)c
1
2
3
1 h
5 min
18 h
80 (14:1)
38 (12:1)
54 (14:1)
10:1
1:1.5
1.2:1
a MgCl2 was allowed to precomplex with THF and phthalic anhydride at 20 °C
for the age time. b Assay yield of desired regioisomer by quantitative HPLC
(thiophene regioselectivity in parentheses). c Molar ratio by quantitative HPLC.
A Direct Magnesiation Approach. A more direct approach
to 2b which would circumvent issues with transmetalation
would be the use of a Mg-TMP amide generated directly from
a magnesium base such as i-PrMgCl. This approach has been
designed for magnesiation of functionalized aryl10 and het-
eroaryl11 rings, including thiophene itself. However, the special-
ized complex base i-PrMgCl·LiCl and stoichiometric levels of
TMP-H are impractical, and reaction times are typically in
excess of 48 h, precluding the use of this system on large scale.
Control experiments indicated that i-PrMgCl could not depro-
tonate 3-methylthiophene by itself.12
anhydride/MgCl2/THF mixtures were used immediately or aged
longer than 6 h, significant amounts of undesired side product
5 were formed (entries 2-3).
The effect shown in Table 1 can be explained by kinetic
solubility of MgCl2/THF complexes,8 where competing
crystal forms have been shown to drastically alter solubil-
ity (eq 1).
fast
slow
MgCl2fMgCl2 ·(THF)2 f MgCl2 ·(THF)4
(1)
highly
sparingly
soluble
soluble
The simultaneous Mg-TMP formation/deprotonation of
3-methylthiophene was investigated as a one-pot process
(Scheme 3). Mg-thiophene formation proceeded with catalytic
(10 mol %) TMP-H;13 however the deprotonation was slow
and incomplete, achieving only 85% conversion after 36 h at
66 °C.14 Once formed, the resulting Mg-thiophene 2b reacted
with phthalic anhydride 3 to produce keto acid 4 in 81% assay
yield with >40:1 regioselectivity favoring the 2,4-disubstituted
thiophene. As expected, exclusive chemoselectivity was main-
tained in this magnesiation/acylation.
Our trend suggests that the highly soluble MgCl2 · (THF)2
complex promotes the desired Li-to-Mg transmetalation,
while side-product formation competes in the presence of
the less soluble MgCl2 · (THF)4 complex. Given the longer
cycle times anticipated on scale, it would be difficult to
rely on a transient kinetic form in a manufacturing
environment. For this reason, lithiation/transmetalation
protocols were abandoned in favor of a direct magnesiation
of 3-methylthiophene.9
Scheme 2. Divergent reactivity of Li- and Mg-thiophenes
(8) Handl´ırˇ, K.; Holecˇek, J.; Benesˇ, L. Collect. Czech. Chem. Commun.
1985, 50, 2422–2430.
(9) Using the solvent DME resulted in a 1:1.4 ratio of 4:5, possibly
indicating a destabilization of alkoxide 7b.
(10) (a) Lin, W.; Baron, O.; Knochel, P. Org. Lett. 2006, 8, 5673–5676.
(b) Stoll, A. H.; Knochel, P. Org. Lett. 2008, 10, 113–116. (c)
Rohbogner, C. J.; Clososki, G. C.; Knochel, P. Angew. Chem., Int.
Ed. 2008, 47, 1503–1507.
(11) (a) Krasovskiy, A.; Krasovskaya, V.; Knochel, P. Angew. Chem., Int.
Ed. 2006, 45, 2958–2961. (b) Clososki, G. C.; Rohbogner, C. J.;
Knochel, P. Angew. Chem., Int. Ed. 2007, 46, 7681–7684. (c) Mosrin,
M.; Knochel, P. Org. Lett. 2008, 10, 2497–2500. (d) Piller, F. M.;
Knochel, P. Org. Lett. 2009, 11, 445–448.
(12) For a relevant discussion, see: Shen, K.; Fu, Y.; Li, J.-N.; Liu, L.;
Guo, Q.-X. Tetrahedron 2007, 63, 1568–1576.
1
(13) Extent of deprotonation measured by H NMR upon quenching with
CD3OD. Similar experiments with iodine were inconsistent with
CD3OD, indicating competitive electrophilic iodination of the Me-
substituted alkene.
(14) No change in rate was observed with i-PrMgCl · LiCl instead of
i-PrMgCl.
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Scheme 3. Design of a catalytic Mg-TMP-promoted
deprotonation/acylation of 3-methylthiophene
Figure 1. Simplified model for proton transfer via coordination
to TMP-H.
reversible process.16 Employing stoichiometric TMP-H sup-
ported this hypothesis, resulting in only 44% conversion (entry
6).
Ultimately, excess 3-methylthiophene (1.2 equiv, or 0.85
equiv of i-PrMgCl, entry 7) drove this equilibrium to product,
resulting in >95% conversion of i-PrMgCl to Mg-thiophene 2b.
The excess 3-methylthiophene showed no detrimental effects
on the acylation step and could be removed during workup
through distillation.17
Additional experimental evidence supports the reversibility
of the magnesiation of 3-methylthiophene. Charging 0.4 equiv
of TMP-H to a reaction at 87% conversion resulted in partial
reversion of 2b to the protonated 3-methylthiophene 1 (ac-
companied by a loss of regioselectivity, see Figure 1). On the
basis of pKa measurements this would be impossible (in DMSO/
TMP-H ) 37, unsubstituted thiophene ) 3212). However,
coordination of a metal complex (in the simplest case, 2b) could
lower the pKa of TMP-H, providing a means for proton
transfer.18 In this hypothesis, the 2-Mg-3-Me-thiophene isomer
would be less likely to participate, providing a rationale for the
observed decay in regioselectivity.
Table 2. Mechanism and optimization
Application of this two-pot magnesiation/acylation to the
synthesis of thiophene-phthalazinone 6 is illustrated in Scheme
4. Treatment of 147 g of 3-methylthiophene with i-PrMgCl as
limiting reagent at 66 °C in the presence of catalytic TMP-H
resulted in 98% conversion to Mg-thiophene 2b.19 Mg-
thiophene 2b (1.10 equiv) was added dropwise to a -20 °C
slurry of phthalic anhydride in THF to provide crude keto acid
4 in 94% assay yield20 (>40:1 thiophene regioisomers). Removal
of solvent and residual 3-methylthiophene was accomplished
through a distillative solvent switch into EtOH. Intermediate 4
was crystallized from EtOH/water in 89.7% adjusted yield.
Alternatively, the crude EtOH solution proved competent
in a through-process conversion to phthalazinone 6. The EtOH
solution of 4 was treated with excess aqueous hydrazine at 80
°C. After consumption of the starting material, the precipitated
product was filtered directly from the reaction at 20 °C. This
process provided thiophene-phthalazinone 6 in 84.7% yield over
the two steps.
entry RMgCl (equiv) equiv of TMP-H % deprotonationa (h)
1
2
3
4
5
6
7
i-PrMgCl (1.1)
i-PrMgCl (1.0)
i-PrMgCl (1.3)
t-BuMgCl (1.0)
n-HexMgCl (1.0)
i-PrMgCl (1.1)
i-PrMgCl (0.85b)
0.1
0.2
0.1
0.2
0.2
1.1
0.1
85 (36)
83 (15)
80 (18)
9 (18)
90 (8)
44 (18)
>95 (18)c
a Measured by 1H NMR after quenching with CD3OD. b Equals 1.2 equiv of
3-methylthiophene, relative to i-PrMgCl. c Based on conversion of i-PrMgCl.
With proof of principle in hand, a detailed study was initiated
to optimize the 3-methylthiophene magnesiation. Increasing the
amount of TMP-H or i-PrMgCl (Table 2, entries 2 and 3) also
increased the deprotonation rate but failed to promote full
conversion. Altering the sterics of the Grignard had a more
profound effect: t-BuMgCl (entry 4) resulted in minimal
deprotonation, while the less-hindered n-HexMgCl promoted
90% conversion to 2b in 8 h.15 This indicates that Mg-TMP
formation may be the rate-limiting step in the catalytic cycle.
Even with an accelerated rate, however, full conversion was
not observed, suggesting that thiophene metalation might be a
(16) For reversible metalation of other heterocycles, see: (a) Comins, D. L.;
LaMunyon, D. H. Tetrahedron Lett. 1988, 29, 773–776. (b) Tre´court,
F.; Mallet, M.; Marsais, F.; Que´guiner, G. J. Org. Chem. 1988, 53,
1367–1371. (c) Viciu, M. S.; Gupta, L.; Collum, D. B. J. Am. Chem.
Soc. 2010, 132, 6361–6365.
(17) Use of excess i-PrMgCl (g1.3 equiv) is detrimental to phthalic
anhydride addition, producing a side product from isopropyl incor-
poration into keto acid product 4.
(18) Magnesium or lithium aggregates have been implicated in reversible
metallations of this type. See references 16a-c and references within
for more details.
(19) The 98% conversion is calculated on the basis of the limiting reagent
i-PrMgCl.
(20) Yield and equivalents are based on the limiting reagent phthalic
anhydride.
(15) Residual n-hexane complicated the through-process synthesis of
phthalazinone 6 (oiling during crystallization) and was abandoned for
the synthesis of this particular target. Further investigation of n-
hexylmagnesium chloride in similar applications is underway.
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Scheme 4. Intermediate scale-up of
thiophene-phthalazinone 6
preliminary survey, the most appropriate heterocycles possess
acidic protons in the approximate pKa range of 27-33. It is
important to note that the one-pot Mg-TMP formation/depro-
tonation sequence is not compatible with substrates that undergo
nucleophilic attack by i-PrMgCl under these conditions (i.e.,
quinoline, isoquinoline, thiazole) or substrates susceptible to
metal-halogen exchange (i.e., 2-chloropyridine, 2-chloropyri-
midine). Nevertheless, this method provides a means for rapid
installation of select heterocycles into more complex chemical
frameworks via the metalated heterocycle, utilizing bench-stable
commercial reagents and scalable conditions.
Conclusion
In summary, a commercially viable regioselective deproto-
nation of 3-substituted thiophenes based on the inexpensive base
i-PrMgCl and substoichiometric TMP-H has been developed.
This protocol replaces lithium-based methods using stoichio-
metric amine additives and cryogenic conditions. This study
revealed the divergent reactivity of lithio- and magnesio-
thiophene reagents toward cyclic anhydrides, and identified a
dynamic solvation effect that influences MgCl2/THF-promoted
transmetalations. Importantly, this magnesiation process displays
excellent compatibility with cyclic anhydrides, unlike similar
Li or Li/Mg systems. Mechanistic studies have also established
the reversibility of the Mg-TMP promoted deprotonation of
3-methylthiophene. Together, these findings have enabled a
practical, regioselective, and chemoselective synthesis of a target
thiophene-phthalazinone 6 in 84.7% yield (two steps, one
isolation) from inexpensive commercially available materials.
Table 3. Magnesiation with Mg-TMP and reaction with
electrophiles
Experimental Section
General. i-PrMgCl quality was monitored by titration versus
menthol, using 1,10-phenanthroline as indicator.21 Reactions
were conducted under an atmosphere of nitrogen with a suitable
outlet to accommodate modest pressure changes. Reaction
temperatures were monitored by an internal thermocouple.
Reaction progress and compound purity were determined by
HPLC analysis, using an Eclipse XDB C8, 4.6 mm × 150 mm,
5 µm column, with a gradient method using 0.1% (v/v) 70%
HClO4/water and acetonitrile as mobile phase. Purity was
assessed using high-purity reference standards and confirmed
1
by quantitative H NMR. HRMS (ESI-TOF) spectra were
obtained using Agilent 1100 systems.
a Formation: 1.4 equiv heterocycle, 1.0 equiv of i-PrMgCl, 0.1 equiv of
TMP-H, THF, 66 °C, 18 h. b Isolated yield after chromatography (not optimized).
c Assay yield after workup.
2-(4-Methylthiophene-2-carbonyl)benzoic Acid (4). 2,2,6,6-
Tetramethylpiperidine (25.2 mL, 150 mmol) was charged in
one portion to 3-methylthiophene 1 (147 g, 144 mL, 1500
mmol) in THF (576 mL). iso-Propylmagnesium chloride (2.00
M solution in THF, 633 mL, 1270 mmol) was added over 10
min at <30 °C. The resulting solution was heated to reflux at
To examine the reactivity of this metalated heterocycle,
preformed Mg-thiophene 2b was subjected to a number of
electrophiles at 0 °C. As shown in Table 3, this reagent provided
moderate yield of the resulting bifunctional thiophenes 9a-e,
indicating compatibility with a range of electrophiles. In all
cases, the products were formed with excellent (>40:1) regi-
oselectivity, favoring the 2,4-disubstituted thiophene product.
Similarly, the one-pot catalytic TMP-H/i-PrMgCl mediated
deprotonation is amenable to heterocycles bearing appropriately
acidic protons. Several heterocyclic thiophene and benzothiazole
magnesium reagents 8a-d were generated via this protocol and
shown to possess similar reactivity to 2b. On the basis of this
1
66 °C. After 23 h, H NMR analysis of a reaction aliquot
quenched with CD3OD indicated 98%19 conversion to the Mg-
thiophene 2b (96.8% 2-D-4-methylthiophene, 1.2% 2-D-3-
methylthiophene of theoretical 0.85 equiv). The Mg-thiophene
solution was cooled to 20 °C. Phthalic anhydride 3 (170 g, 1150
mmol) in THF (720 mL) was charged to a separate flask, and
the resulting slurry was cooled to -20 °C. The Mg-thiophene
(21) Lin, H.-S.; Paquette, L. A. Synth. Commun. 1994, 24, 2503–2506.
See Supporting Information for a detailed procedure.
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solution (at 20 °C) was added to the phthalic anhydride slurry
over 45 min, at -25 to -20 °C. After 20 min, the reaction
was quenched with H2O (510 mL) added over 10 min between
-20 and 10 °C,22 followed by 6 N HCl (289 mL) to pH 2. The
reaction mixture was warmed to 20 °C, and MTBE (289 mL)
was added. After 10 min, the layers were separated; the upper
organic layer was assayed to 267 g keto acid 4 (94.1%20).
The crude keto acid 4 was concentrated by distillation (60
°C, 350 mbar) to 530-545 mL, and the resulting pot was
maintained at 60 °C. Ethanol (1070 mL) was added, and the
solution was distilled again to 530-545 mL total volume. HPLC
analysis of the distillate revealed 3-methylthiophene as the only
UV-active component. After breaking vacuum, ethanol (800
mL) was charged and the flask was cooled to 20 °C over 3 h.
Water (1330 mL) was added over 2 h, and then aged for 10 h.
The slurry was filtered, and the cake was displacement-washed
with 25% EtOH/H2O (535 mL). The collected mother liquors
and wash contained 11.6 g (4.1%) product 4. The solid was
dried on the frit at 20 °C for >24 h, under a nitrogen stream, to
provide keto acid 4 as an off-white solid (261 g, 97.3 wt %,
89.7% adjusted yield). 1H NMR (DMSO-d6, 400 MHz) δ 13.16
(br s, 1H), 7.96 (ddd, J ) 0.5, 1.5, 7.5 Hz, 1H), 7.64-7.72 (m,
3H), 7.49 (ddq, J ) 0.6, 1.5, 7.5 Hz, 1H), 7.09 (dq, J ) 0.4,
1.5 Hz, 1H), 2.18 (dd, J ) 0.4, 0.6 Hz, 3H); 13C NMR (DMSO-
d6, 400 MHz) δ 188.5, 166.9, 143.6, 140.7, 138.6, 136.1, 132.1,
130.7, 129.9, 129.9, 129.8, 127.4, 15.0; HRMS calculated for
C13H9O2S1 [M + H - H2O]+ 229.0318, found 229.0316; IR
(neat): 3050, 2970, 2920, 1690 cm-1; mp: 191 °C.
solution was distilled again to 180-190 mL total volume. After
breaking vacuum, ethanol (367 mL) was charged to the reaction
and the flask was cooled to 20-30 °C. To the resulting solution
was added hydrazine (35 wt % solution in H2O, 169 mL, 1870
mmol) over 10 min, at 35 °C. The reaction was heated to 80
°C for 18 h, until HPLC assay of the resulting slurry indicated
>95% conversion to product.23
The reaction was cooled to 20 °C over 2 h and then aged at
20 °C for 1 h. The resulting slurry was filtered, and the cake
was displacement-washed with 50% EtOH/H2O (180 mL). The
cake was dried under N2 stream at 20 °C to give 82.7 g
thiophene-phthalazinone 6 as a pale-yellow solid (98.6 wt %,
84.7% adjusted yield over two steps). The collected mother
liquors and wash contained 1.78 g of product 6 (1.9%) and
5.70 g of keto acid 7 (6.1%). 1H NMR (CDCl3, 400 MHz) δ
2.38 (d, J ) 0.8, 3H), 7.09 (dq, J ) 0.8, 1.1, 1H), 7.28 (d, J )
1.1, 1H), 7.86 (m, 2H), 8.17 (m, 1H), 8.53 (m, 1H), 10.31 (bs,
1H); 13C NMR (CDCl3, 100 MHz) δ 15.83, 122.91, 126.63,
127.08, 128.22, 129.38, 130.88, 131.71, 133.70, 136.33, 138.14,
142.43, 159.72; mp: 232 °C.
Acknowledgment
We thank Kelly Nadeau and Karl Hansen for helpful
discussions.
Supporting Information Available
Procedures and representative NMR spectra for compounds
4, 6, and 9. This material is available free of charge Via the
Internet at http://pubs.acs.org.
4-(4-Methylthiophene-2-yl)phthalazine-1(2H)-one (6). Cru-
de keto acid 4 (91.9 g) was synthesized as described above.
The crude MTBE/THF layer was concentrated by distillation
(60 °C, 300 mbar) to 180-190 mL, and the resulting pot was
maintained at 60 °C. Ethanol (367 mL) was added, and the
Received for review August 13, 2010.
OP100226K
(23) This reaction proceeds below the flash point of 35% hydrazine/water
(112.7 °C) and below the boiling point of a hydrazine/water azeotrope
(120.3 °C). DSC and ARC scanning of the reaction components at
300 and 250 °C, respectively, showed no unsafe thermodynamic
events.
(22) In a power compensation calorimetry experiment conducted at 10 °C
isothermal, quenching the reaction with water (4 volumes over 1 h,
60.6 mmol scale) resulted in a 74 kJ/mol exotherm, uncorrected for
heat of mixing.
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