A concise synthesis of 3,4-fused spiro[isobenzofuran-3-ones], spiro[furo[3,4-b]pyridin-5(7H)-ones], 3-aryl-, and alkylphthalides

Article abstract of DOI:10.1016/j.tet.2013.02.051

A synthetically useful protocol has been developed for the preparation of highly functionalized 3,4-fused spiro[isobenzofuran-3-ones], spiro[furo[3,4-b]pyridin-5(7H)-ones], 3-aryl-, and alkylphthalides. Reaction of 2-iodobenzoate esters and 2-iodopyridine carboxylate esters with i-PrMgCl·LiCl in the presence of cyclic ketones under standard Barbier reaction conditions affords 3,4-fused spiro[isobenzofuran-3-ones] and spiro[furo[3,4-b]pyridin-5(7H)-ones] in good to excellent yields. Step-wise addition of i-PrMgCl·LiCl to 2-iodobenzoate esters followed by trapping with various aldehydes yields 3-aryl and 3-alkylphthalides; whereas, under similar conditions access to 3-aryl and 3-alylazaphthalides is also possible. Extension of this methodology toward the preparation of 3-n-butylphthalide and chrycolide, a natural product isolated from the leaves and stems of Chrysanthemum coronarium, is also described.

Full text of DOI:10.1016/j.tet.2013.02.051

Tetrahedron 69 (2013) 5248e5258
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Tetrahedron
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A concise synthesis of 3,4-fused spiro[isobenzofuran-3-ones], spiro
[furo[3,4-b]pyridin-5(7H)-ones], 3-aryl-, and alkylphthalides
*
*
Jeffrey T. Kuethe , Kevin M. Maloney
Department of Process Research, Merck & Co., Inc., P.O. Box 2000, Rahway, NJ 07065, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A synthetically useful protocol has been developed for the preparation of highly functionalized 3,4-fused
spiro[isobenzofuran-3-ones], spiro[furo[3,4-b]pyridin-5(7H)-ones], 3-aryl-, and alkylphthalides. Reaction
of 2-iodobenzoate esters and 2-iodopyridine carboxylate esters with i-PrMgCl$LiCl in the presence of
cyclic ketones under standard Barbier reaction conditions affords 3,4-fused spiro[isobenzofuran-3-ones]
and spiro[furo[3,4-b]pyridin-5(7H)-ones] in good to excellent yields. Step-wise addition of i-PrMgCl$LiCl
to 2-iodobenzoate esters followed by trapping with various aldehydes yields 3-aryl and 3-
alkylphthalides; whereas, under similar conditions access to 3-aryl and 3-alylazaphthalides is also
possible. Extension of this methodology toward the preparation of 3-n-butylphthalide and chrycolide,
a natural product isolated from the leaves and stems of Chrysanthemum coronarium, is also described.
Ó 2013 Elsevier Ltd. All rights reserved.
Received 3 December 2012
Received in revised form 14 February 2013
Accepted 18 February 2013
Available online 13 March 2013
1. Introduction
3 are a common structural motif utilized in drug discovery2 and
have been classified as ‘privileged structures’ due to their rigid
Spiro isobenzofurans 1 and furopyridines 2, and their dihydro-
counterparts,1 constitute the central pharmacophore of an emerg-
ing class of heterocyclic compounds possessing a range of biological
activities (Fig. 1). In particular, spiropiperidines of general structure
structure and ability to direct functional groups in well-defined
spaces.3 The closely related phthalides 4 are found in abundance
in nature4 as well as in many biologically active compounds5 and
are also utilized extensively in medicinal chemistry. Interestingly,
azaphthalides of type 5 have remained relatively unexplored and
access to these structurally intriguing molecules has not been fully
reported.
The most commonly employed method for the preparation of
compounds 1e3 involve metalehalogen exchange of 2-(2-
bromophenyl)-4,40-dimethyloxazolines (Meyers method),6 2-
bromobenzamides,7 2-bromobenzoic acid,8 or 2-bromopyridine-
3-carboxylic acids.9 While suitable for the preparation of simple
substrates, the use of butyllithium in conjunction with other sen-
sitive functionalities render these protocols limited in scope. A
three step sequence involving a Suzuki coupling, iodolactonization,
and reduction for the preparation of variously substituted furo-
pyridines 3 has been disclosed.10 Mild synthetic methods that allow
for assembly of these heterocycles and tolerate a wide range of
functional groups continue to offer significant advantages. Recently
we required significant quantities of compound 6 to support de-
velopment of a drug candidate and needed to develop a practical
procedure for its preparation on larger scale. It was envisioned that
a suitably functionalized ortho-iodopyridyl ester or nitrile 8a/
b would allow for Grignard formation in the presence of ketone 7
followed by intramolecular cyclization leading to 6, potentially in
a one-pot manner (Scheme 1). In this paper, we document a com-
plete account of our work in this area, including the preparation of
Fig. 1. 3,4-Fused spiro[isobenzofuran-3-ones], spiro[furo[3,4-b]pyridin-5(7H)-ones], 3-
aryl- and alkylphthalides.
* Corresponding authors. E-mail addresses: Jeffrey_Kuethe@merck.com (J.T.
Kuethe), Kevin_Maloney@merck.com (K.M. Maloney).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.02.051

J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
5249
compounds of general type 1e5 and highlight the methodology
with the efficient preparation of natural products 3-n-butylph-
thalide and chrycolide, a plant growth inhibitor isolated from
Chrysanthemum coronarium.
ketone 7 and subsequent hydrolysis with MeOH/AcOH furnished
lactone 6 in 57% isolated yield. Analysis of the crude reaction
mixture prior to isolation of 6 revealed the presence of 11 (w35%).
The use of i-PrMgCl$LiCl was next examined and was found to give
higher yields of 6 (up to 65%) with a corresponding reduction in the
amount of 11 (w25%) being formed during the reaction. Finally, we
discovered that conducting the reaction under Barbier conditions
further improved the reaction yield by decreasing the level of 11 to
ca. 10% (Scheme 3). The final optimized procedure for the prepa-
ration of 6 involved treatment of a mixture of 8b and ketone 7
(1.4 equiv) with i-PrMgCl$LiCl (1.4 equiv) in THF at ꢀ50 ꢁC followed
by warming to room temperature and quenching with 1:1 MeOH/
AcOH (7 equiv) (Scheme 3). After heating to 50 ꢁC to affect cycli-
zation and an aqueous workup, spirolactone 6 was isolated by
crystallization from aqueous IPA in 79% yield. The mass balance of
the reaction was 11, which proved to be unavoidable due to com-
petitive deprotonation of 7. Attempts to use CeCl3 or LnCl3 to acti-
vate ketone 7 toward 1,2 addition and further suppress enolization
(formation of 11) were completely unsuccessful.15 Given the sim-
plicity with which the reaction was conducted and the structural
complexity achieved, the optimized yield of 6 was deemed
acceptable.
In order to understand the mechanistic aspects of the formation
of 11 under the optimal conditions, a series of experiments were
devised to probe whether enolization was indeed occurring or if the
formation of 11 was a result of quenching of the intermediate
Grignard reagent upon workup (Scheme 4). For example, treatment
of 12 with i-PrMgCl$LiCl (1.4 equiv) in THF at ꢀ50 ꢁC followed by
addition of piperidone 13 and warming the reaction to room
temperature lead to the formation of 14 (67%). The reaction mixture
was then quenched with D2O and the crude organic layer was an-
alyzed by GCeMS, which indicated almost the exclusive formation
of 15 and only trace amounts (<3%) of 16 (Scheme 4). Further
analysis of the crude reaction mixture by 1H NMR did not reveal any
deuterium incorporation into 13. To further demonstrate that
competitive enolization of 13 (and 7 above) was the source of the
formation of 15, the reaction was repeated under the identical re-
action conditions using perdeuterated piperidone 17.16 Analysis of
Scheme 1.
2. Results and discussion
2.1. Preparation of 3,4-fused spiro[isobenzofuran-3-ones]
and spiro[furo[3,4-b]pyridin-5(7H)-ones]
Our investigations began by examining the reaction between
iodide 8b11 and ketone 7 (Scheme 2). Initial efforts were focused on
metalehalogen exchange employing n-BuLi at low temperature
(ꢀ78 ꢁC) followed by quenching with 7 and warming to room
temperature. Examination of the crude reaction mixture by HPLC
and LC/MS showed that the major product was alcohol 10 (w50%).
Also detected in the crude reaction mixture was desiodopyridine 11
(27%) and the desired product 6 in 7% yield together with a number
of by-products that were not identified. Direct addition of an excess
of MeOH and AcOH to the crude reaction mixture followed by
warming to 60 ꢁC resulted in cyclization of 10 to give 6 in 38%
isolated yield. We also examined the use of Bu2Mg and a combi-
nation of n-BuLi/Bu2MgCl.12 In each case the reaction profile was
similar to that when n-BuLi was employed and the isolated yields of
6 never exceeded 40%. The formation of 11 as a major reaction by-
product under these conditions suggested that competitive
deprotonation of 7 was taking place leading to diminished yields of
the desired product (vide infra).
Δ
Scheme 2.
The pioneering work by Knochel and co-workers has demon-
strated that under particularly mild reaction conditions, halogen-
emagnesium exchange is facile and tolerant of a wealth of
functional groups.13 Typically i-PrMgCl is utilized for halogen-
emagnesium exchange; however, due to its magnesiate character
and enhanced reactivity, i-PrMgCl$LiCl often proves to be the su-
perior reagent.14 We set out to explore the use of these reagents in
an attempt to improve the reaction profile and yield of 6. Treatment
of 8b with i-PrMgCl at ꢀ50 ꢁC in THF followed by trapping with
the crude reaction mixture by GCeMS revealed both the formation
of 15 and 16 in an approximated 3:2 ratio. Compound 18 was ob-
tained in 71% isolated yield after chromatography. The formation of
15 was not completely surprising as the isotopic purity of 17
employed in the experiment existed as 66:27:6.4:0.5:0.1 ratio of
D4:D3:D2:D1:D0 as determined by LCeMS. Due to the kinetic iso-
tope effect of deuterium, it would be expected that proton extrac-
tion from D3eD1 containing 17 would be faster than deuterium
extraction leading the formation of observed 15. Therefore, it is

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J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
Scheme 3.
Scheme 4.
reasonable to conclude that proton extraction of 7, 13, and 17 is
a competitive process leading to slightly diminished yields of the
products.
balance of each reaction was dehalogenation via competitive pro-
ton extraction from the ketones.
Having established a productive synthesis of 6, which was
successfully applied on kilogram scale, we set out to explore the
application of this methodology in the preparation of other 3,4-
fused spiro[isobenzofuran-3-ones] and spiro[furo[3,4-b]pyridin-
5(7H)-ones. The results are highlighted in Table 1. For example,
reaction of iodoester 12 with either ketone 7 or 20 in THF and in the
presence of i-PrMgCl$LiCl under Barbier conditions lead to excel-
lent yields of the expected spirolactones 19 and 21. In similar
fashion, reaction of 12 with cyclohexanone and cyclopentanone
afforded 23 and 25 in 83% and 57% yields, respectively. Grignard
addition to ketone 26 followed by cyclization proceeds in excep-
tionally good yield to give 27 in 90% isolated yield. Interestingly,
reaction of 28 with i-PrMgCl$LiCl in the presence of ketone 7 did
not give any of the expected cyclization product 29 and dehaloge-
nation of 28 was the only observed reaction. We speculate that the
intermediate Grignard is particularly stable and addition to 7 does
not take place (entry 6). Instead, proton extraction from 7 was the
predominate reaction pathway. On the other hand, reaction of 30
with 7 in the presence of n-BuLi was successful and, after hydrolysis
of the intermediate addition products with MeOH/AcOH, spi-
rolactone 29 was obtained in 51% yield. Iodoindole 31 also served as
a useful substrate leading to the formation of the novel and highly
functionalized spiro-indolelactones 32 (63%) and 33 (67%). It
should be noted in all cases, except entry 7, that upon addition of i-
PrMgCl$LiCl and warming to room temperature, cyclization to the
corresponding spirolactones occurred without the need for a sec-
ondary acid-mediated cyclization step. Furthermore, the mass
2.2. Preparation of 3-aryl and alkylphthalides
As a further extension, we investigated the formation of both 3-
aryl- and alkylphthalides. While there are a number of methods
reported for the preparation of 3-substituted phthalides,17 re-
actions of 2-iodoesters and nitriles with i-PrMgCl$LiCl and alde-
hydes for the preparation of these important pharmacophores has
been relegated to a few isolated reports.14,18 Our investigations
began with the treatment of 12 with i-PrMgCl$LiCl at ꢀ60 ꢁC for
15 min followed by the addition of 34 and warming the reaction
mixture to room temperature (Scheme 5). After an aqueous
workup, phthalide 35 was obtained in 91% yield. An alternative
preparation of 35 was also investigated. Reaction of 36 with i-
PrMgCl$LiCl at ꢀ60 ꢁC for 15 min followed by addition of 37 and
warming to room temperature gave 35 in 64% yield. The application
of this process for the preparation of a range of phthalides is shown
in Table 2. The yields of these phthalides were uniformly high and
provided access to functionalized intermediates bearing suitable
handles for further manipulation (entries 2e5). Entry 5 demon-
strates the high iodide selectivity during the halogenemagnesium
exchange reaction of 46 giving rise to phthalide 48 after quenching
with aldehyde 47. Even alkyl aldehydes are suitable substrates as
demonstrated by the preparation of 3-alkylphthalide 50 (entry 6).
Extracted from celery seed oil,19 3-n-butylphthalide 52 is an active
ingredient in Chinese folk medicine that has been approved by the
State Food and Drug Administration (SFDA) of China for the treat-
ment of ischemic stroke.20 It has also been used in flavoring and

J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
Table 1 (continued )
5251
Table 1
3,4-Fused spiro[isobenzofuran-3-ones] and spiro[3,4-b]pyridine-5(7H)-ones
Entry
Iodide
Electrophile
Product
Yield
Entry Iodide Electrophile Product
Yield
1
84%
8
63%
2
3
4
75%
83%
57%
9
67%
seasoning. In addition, 3-n-butylphthalide 52 has been shown to
increase the duration of anesthesia,21 to have anticonvulsant ac-
tion,22 may have neuroprotective affects,23 and has been studied for
the treatment of hypertension.24 There have been a number of
syntheses reported including asymmetric syntheses.25 We envi-
sioned a one-pot single step synthesis of 52 starting from iodide 12
and readily available valeraldehyde 51 (Table 2, entry 7). Reaction of
12 with i-PrMgCl$LiCl in THF at ꢀ60 ꢁC for 15 min followed by
quenching with 51 and warming to room temperature gave racemic
3-n-butylphalide 52 in 82% yield after purification by silica gel
chromatography. Nitriles may also be employed (entry 8), but re-
quire hydrolysis with MeOH/AcOH to effect cyclization to lactone
54. In the case of iodoindole 31 did cyclization prove problematic
and only secondary alcohol 55 was isolated in 90% yield. All at-
tempts to close the lactone ring (MeOH/AcOH or NaH) proved un-
successful and did not afford the desired product.
2.3. Preparation of 3-aryl and alkylazaphthalides
5
90%
We next turned our attention to synthesis of relatively unknown
azaphthalides (Scheme 6).26 For example, reaction of 28 with i-
PrMgCl$LiCl at ꢀ60 ꢁC followed by quenching with piperonal 38
and warming the reaction mixture to room temperature resulted in
the exclusive formation of intermediate 56, which could be isolated
after an aqueous workup in 90% yield.27 There was no evidence of
further cyclization to azaphthalide 57 observed in both the crude
1H NMR or by HPLC analysis. Unlike the reaction of 28 in the
presence of ketones where no reaction occurs (Table 1, entry 6),
addition of the Grignard of 28 to aldehyde 38 is facile leading to 56.
Cyclization to 57 was accomplished by direct addition of MeOH/
AcOH (7 equiv each) to the crude reaction mixture and heating to
60 ꢁC for several hours to drive the reaction to completion, which
gave 57 in 83% yield for the one-pot process. In like fashion,
azaphthalides 58, 59, 61, and 63 were prepared in good to excellent
yield (Table 3) providing access to aryl (entries 1e3) and alkyla-
zaphthalides (entry 4).
6
0%
7
51%
2.4. Application to natural product synthesis
Having established the synthetic utility of the process, we
highlighted the synthetic protocol toward natural product syn-
thesis. Isolated from leaves and stem of a popular vegetable (C.

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J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
Scheme 5.
coronarium, Japanese name: shugiku) in China and Japan, chryco-
lide 70 has been shown to have plant growth inhibiting activity.28
To date there have been no reported total synthesis of chrycolide
70 and the absolute configuration has yet to be established. Our
first attempted synthesis of chrycolide 70 began with iodo-
fluoroester 64 (Scheme 7). Treatment of 64 with i-PrMgCl$LiCl in
THF at ꢀ70 ꢁC for 15 min followed by quenching with 2-
thiophenecarboxaldehyde 66 and warming to room temperature
gave thienylphthalide 66 in 78% isolated yield. Attempted nucleo-
philic aromatic displacement of the fluoride atom in 66 with vari-
ous alcohols was unsuccessful forcing us to explore an alternative
route. The second route started with iodonitrile 68. Treatment of 68
with i-PrMgCl$LiCl in THF at ꢀ70 ꢁC for 15 min followed by
quenching with 2-thiophenecarboxaldehyde 65 and warming to
room temperature gave alcohol 69 in 86% isolated yield. Un-
fortunately, all attempts to cyclize 69 with acid or base to give 67
resulted in complete decomposition. The thienylphthalide moiety
of 66 and 69 is particularly sensitive to any strong acid and leads to
significant degradation of the molecule.29
The successful synthesis of chrycolide began with acid 71
(Scheme 8). Protection of 71 as its tert-butylester proceeded
smoothly and gave 72 in near quantitative yield. Surprisingly, dis-
placement of the aryl fluoride atom with potassium tert-butoxide in
THF occurred smoothly at room temperature to give 73 in 88% yield.
Removal of the tert-butyl protecting groups with TFA and re-
esterification afforded 74 in 90% overall yield for the two steps.
Initially, we believed that protection of the phenol was required
prior to formation of the phthalide ring system. Therefore, reaction
of 74 with TBDMS-Cl and treatment with i-PrMgCl$LiCl and
quenching with 2-thiophenecarboxaldehyde 65 afforded the ex-
pected product in good overall yield. Finally, removal of the silyl
protecting group with TBAF gave chrycolide 70 in 82% yield from 74.
With a synthetic route in place, we set out to shorten the synthesis
by looking at the direct conversion of 74 to chrycolide 70. Much to
our delight, reaction of 74 with 1 equiv of sodium hydride followed
by 1 equiv of i-PrMgCl$LiCl in THF at ꢀ70 ꢁC and trapping the in-
termediate with 65 furnished 70 in 92% yield for the single step
process thus eliminating two steps from the sequence. The five step
total synthesis of (ꢂ)-chrycolide proceeded in 71% overall yield
from iodoacid 71. The 1H and 13C NMR, melting point, and UV of our
synthetic chrycolide were in complete agreement with that re-
ported for natural chrycolide and thus this represents the first total
synthesis of this natural product.
aryl and alkylphthalides including the azaphthalides. The reaction
conditions are mild and tolerant of a range of functionality leading
to increasing molecular complexity in a single chemical trans-
formation. Finally, the synthetic protocol was highlighted by the
one-pot synthesis of 3-n-butylphthalide and the first reported total
synthesis of chrycolide.
4. Experimental section
4.1. General
Commercial grade reagents and solvents were used without
further purification. 1H NMR and 13C NMR spectra were measured
with a 400 MHz spectrometer. 1H NMR chemical shifts are
expressed in parts per million (
(with the CHCl3 peak at 7.27 ppm used as a standard). 13C NMR
chemical shifts are expressed in parts per million ( ) downfield
d) downfield from tetramethylsilane
d
from tetramethylsilane (with the central peak of CHCl3 at
77.23 ppm used as a standard). Purifications were carried out by
flash column chromatography on a Teledyne Isco CombiFlash Rf
using a gradient elution of 0e100% EtOAc/hexanes unless other-
wise specified.
4.2. General procedure A
A three-necked, round-bottomed flask equipped with a septum,
nitrogen inlet adapter, and thermocouple was charged with the
iodopyridine (1 equiv), ketone (1.0e1.1 equiv), and THF (15 mL per
1 g of iodopyridine). The reaction mixture was cooled at ꢀ50 to
ꢀ70 ꢁC while a solution of isopropylmagnesium chlorideelithium
chloride (1.3 M, 1.1e1.2 equiv) or n-butyllithium (2.5 M, 1.1 equiv)
was added rapidly via syringe and the reaction mixture was
warmed to room temperature. MeOH (7 equiv) and AcOH (7 equiv)
were added and the resulting reaction mixture was stirred at 60 ꢁC
for 2e17 h. After complete cyclization, the reaction mixture was
concentrated and then diluted with EtOAc and satd NaHCO3. The
resulting aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (EtOAc/hexanes) to give the desired
product.
4.3. General procedure B
3. Conclusion
A three-necked, round-bottomed flask equipped with a septum,
nitrogen inlet adapter, and thermocouple was charged with the
iodopyridine (1 equiv) and THF (15 mL per 1 g of iodopyridine). The
reaction mixture was cooled at ꢀ50 to ꢀ70 ꢁC while a solution of
In conclusion, we have outlined an effective strategy for the
preparation of highly functionalized 3,4-fused spiro[iso-
benzofuran-3-ones] and spiro[furo[3,4-b]pyridin-5-(7H)-ones] via
a one-pot Barbier reaction between 2-iodoesters or nitriles with
ketones or aldehydes in the presence of i-PrMgCl$LiCl. The meth-
odology was extended to the synthesis of highly functionalized 3-
isopropylmagnesium
chlorideelithium
chloride
(1.3
M,
1.1e1.3 equiv) was added and the reaction mixture stirred for
30 min. The aldehyde or ketone (1.0e1.3 equiv) was added in one
portion and the reaction mixture was warmed to room

J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
Table 2 (continued )
5253
Table 2
3-aryl- and alkylphthalides
Entry
Iodide
Aldehyde
Phthalide
Yield
Entry
Iodide
Aldehyde
Phthalide
Yield
8
78%
1
89%
2
3
4
77%
82%
90%
9
90%
Scheme 6.
5
6
7
70%
95%
82%
temperature. After complete cyclization, water was added and the
aqueous layer was extracted with EtOAc. The organic layer was
washed with brine, dried over MgSO4, filtered, and concentrated.
The residue was purified by column chromatography (EtOAc/hex-
anes) to give the desired product.
4.4. General procedure C
A three-necked, round-bottomed flask equipped with a septum,
nitrogen inlet adapter, and thermocouple was charged with the
iodopyridine (1 equiv) and THF (15 mL per 1 g of iodopyridine).
The reaction mixture was cooled at ꢀ50 to ꢀ70 ꢁC and a solution
of isopropylmagnesium chlorideelithium chloride (1.3 M,
1.1e1.2 equiv) was added and the reaction mixture was stirred for
30 min. The aldehyde or ketone (1.0e1.1 equiv) was added in one
portion and the reaction mixture was warmed to room tempera-
ture. MeOH (7 equiv) and AcOH (7 equiv) were added in one por-
tion and the resulting reaction mixture was stirred at 60 ꢁC for
2e17 h. After complete cyclization, the reaction mixture was

5254
J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
Table 3
4.4.1. tert-Butyl 3-chloro-2-methyl-5-oxo-5H-spiro[furo[3,4-b]pyri-
3-aryl- and alkylazaphthalides
dine-7,40-piperidine]-10-carboxylate (6). According to general pro-
cedure A, treatment of 2.00 g (7.18 mmol) of iodopyridine 8b and
1.57 g (7.90 mmol) of ketone 7 with 6.63 mL (8.62 mmol) of a 1.3 M
solution of i-PrMgCleLiCl afforded 2.01 g (79%) of 6 as light yellow
Entry
Iodide
Aldehyde
Phthalide
Yield
70%
crystals: 1H NMR (CDCl3, 400 MHz)
d
1.51 (s, 9H), 1.67 (d, 2H,
J¼12.9 Hz), 2.25 (td, 2H, J¼13.8, 4.9 Hz), 2.77 (s, 3H), 3.31 (s, 2H),
4.21 (s, 2H), 8.09 (s, 1H); 13C NMR (CDCl3, 100 MHz)
23.8, 28.5,
d
1
33.9, 40.3, 80.0, 85.4, 118.3, 132.7, 133.8, 154.5, 163.6, 166.5, 168.6.
Anal. Calcd for C17H21ClN2O4: C, 57.87; N, 7.94, H, 6.00. Found: C,
57.86; N, 7.95; H, 6.02.
4.4.2. 10-Benzyl-3H-spiro[isobenzofuran-1,40-piperidine]-3-one
(14). According to general procedure B, treatment of 0.70 g
(2.67 mmol) of methyl 2-iodobenzoate 12 with 2.47 mL
(3.20 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 510 mg (2.67 mmol) of ketone 13 gave 525 mg (67%)
2
70%
of 18 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d 1.71 (m, 2H),
2.23 (m, 2H), 2.56 (m, 2H), 2.92 (m, 2H), 3.64 (s, 2H), 7.23e7.39 (m,
5H), 7.42 (d, 1H, J¼7.6 Hz), 7.51 (t, 1H, J¼7.6 Hz), 7.66 (t, 1H,
J¼7.3 Hz), 7.87 (d, 1H, J¼7.3 Hz); 13C NMR (CDCl3, 100 MHz)
d 35.7,
49.5, 63.2, 84.7, 121.1, 125.7, 125.9, 127.2, 128.3, 129.2, 134.1, 138.1,
153.9, 169.7. MS (C20H21NO2): 308.2.0 (MþHþ).
4.4.3. 10-Benzyl-30,30,50,50-tetradeterio-3H-spiro[isobenzofuran-1,40-
piperidine]-3-one (18). According to general procedure B, treat-
ment of 0.66 g (2.52 mmol) of methyl 2-iodobenzoate 12 with
2.33 mL (3.02 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed
by trapping with 0.49 g (2.52 mmol) of ketone 17 gave 532 mg
3
67%
(71%) of 1817a as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d 2.56
(d, 2H, J¼12.0 Hz), 2.92 (d, 2H, J¼11.0 Hz), 3.64 (s, 2H), 7.23e7.39 (m,
5H), 7.42 (d, 1H, J¼7.6 Hz), 7.51 (t, 1H, J¼7.6 Hz), 7.66 (t, 1H,
J¼7.3 Hz), 7.87 (d, 1H, J¼7.3 Hz); 13C NMR (CDCl3, 100 MHz)
d 35.7
(m), 49.5, 63.2, 84.7, 121.1, 125.7, 125.9, 127.2, 128.3, 129.2, 134.1,
138.1, 153.9, 169.7. MS (C20H17D4NO2): 312.2.0 (MþHþ).
4
60%
4.4.4. tert-Butyl 3-oxo-3H-spiro[isobenzofuran-1,40-piperidine]-10-
carboxylate (19). According to general procedure B, treatment of
1.78 g (6.81 mmol) of methyl 2-iodobenzoate 12 with 6.28 mL
Scheme 7.
concentrated and then diluted with EtOAc and satd NaHCO3. The
resulting aqueous layer was separated and extracted with EtOAc.
The combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated. The residue was purified by
column chromatography (EtOAc/hexanes) to give the desired
product.
(8.17 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 1.63 g (8.17 mmol) of ketone 7 afforded 1.73 g (84%)
of 1930 as a white solid: 1H NMR (CDCl3, 400 MHz)
d 1.51 (s, 9H),
1.69 (d, 2H, J¼12.4 Hz), 2.08 (td, 2H, J¼13.7, 5.0 Hz), 3.27 (s, 2H), 3.31
(s, 2H), 4.20 (s, 2H), 7.38 (dt, 1H, J¼7.6, 0.9 Hz), 7.54 (td, 1H, J¼7.5,
0.9 Hz), 7.69 (td, 1H, J¼7.5, 1.1 Hz), 7.90 (dt, 1H, J¼7.6, 0.9 Hz); 13C

J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
5255
Scheme 8.
NMR (CDCl3, 100 MHz)
d
28.4, 35.8, 40.5, 80.0, 84.6, 121.0,
100 MHz)
126.5, 126.6, 128.9, 130.0, 131.1, 132.3, 134.9, 144.9, 167.9; 19F NMR
(CDCl3, 376 MHz)
d
85.6 (d, J¼32 Hz), 123.22 (q, J¼282 Hz), 124.2, 125.9,
125.5, 126.1, 129.5, 134.3, 153.2, 154.7, 169.4. Anal. Calcd for
C17H21NO4$0.5H2O: C, 65.37; N, 4.48, H, 7.10. Found: C, 65.72; N,
4.88; H, 7.49.
d
ꢀ76.3. Anal. Calcd for C15H9F3O2: C, 64.75; H,
3.26. Found: C, 64.48; H, 3.19.
4.4.5. Benzyl 3-oxo-3H-spiro[isobenzofuran-1,40-piperidine]-10-car-
boxylate (21). According to general procedure B, treatment of
2.67 g (10.19 mmol) of methyl 2-iodobenzoate 12 with 8.62 mL
(11.21 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 2.62 g (11.21 mmol) of ketone 20 afforded 2.58 g
4.4.9. tert-Butyl 5-oxo-5H-spiro[furo[3,4-b]pyridine-7,40-piperidine]-
10-carboxylate (29). According to general procedure A, treatment of
2.00 g (8.70 mmol) of iodopyridine 30 and 1.91 g (9.56 mmol) of
ketone 7 with 3.83 mL (9.56 mmol) of a 2.5 M solution of n-BuLi
afforded 1.35 g (51%) of 2910 as white crystals: 1H NMR (CDCl3,
(75%) of 21 as a white solid: 1H NMR (CDCl3, 400 MHz)
d
1.72 (d, 2H,
400 MHz)
d
1.51 (s, 9H), 1.68 (d, 2H, J¼13.6 Hz), 2.27 (td, 2H, J¼13.8,
J¼13.7 Hz), 2.10 (s, 2H), 3.36 (s, 2H), 4.31 (s, 2H), 5.20 (s, 2H),
4.8 Hz), 3.33 (s, 2H), 4.20 (s, 2H), 7.51 (dd, 1H, J¼7.7, 4.8 Hz), 8.20 (d,
7.34e7.41 (m, 6H), 7.55 (t, 1H, J¼7.5 Hz), 7.69 (t, 1H, J¼7.6 Hz), 7.91
1H, J¼8.7 Hz), 8.85 (d, 1H, J¼4.8 Hz); 13C NMR (CDCl3, 100 MHz)
(d, 1H, J¼7.6 Hz); 13C NMR (CDCl3, 100 MHz)
d
35.8, 40.8, 67.5, 84.4,
d 28.4, 33.9, 40.1, 79.9, 85.6, 119.2, 124.3, 134.5, 154.5, 155.2, 167.5,
121.1, 125.5, 126.2, 128.1, 128.2, 128.6, 129.7,134.5, 136.7,153.1, 155.3,
169.3; Anal. Calcd for C20H19NO4$0.5H2O: C, 69.35; N, 4.04, H, 5.82.
Found: C, 69.47; N, 4.28; H, 5.73.
171.1. Anal. Calcd for C17H21ClN2O4: C, 63.14; N, 9.20, H, 6.62. Found:
C, 62.74; N, 9.12; H, 6.57.
4.4.10. 1-tert-Butyl2-ethyl-3-iodo-1H-indole-1,2-dicarboxylate (31). To
a solution of 1.5 g (4.76 mmol) of ethyl 3-iodo-1H-indole-2-
carboxylate32 in 15 mL of CH2Cl2 was added 1.00 mL (7.20 mmol)
of NEt3 and 15 mg (0.123 mmol) of DMAP followed by 1.14 g
(5.24 mmol) of Boc2O. The resulting mixture was stirred at room
temperature overnight and then was concentrated under reduced
pressure. The residue was purified by silica gel chromatography to
afford 1.90 g (96%) of 31 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
4.4.6. 30H-Spiro[cyclohexane-1,10-isobenzofuran]-30-one (23). According
to the general procedure B, treatment of 1.50 g (5.72 mmol) of methyl 2-
iodobenzoate (12) with 4.85 mL (6.30 mmol) of a 1.3 M solution of i-
PrMgCleLiCl followed by trapping with 0.618 g (6.30 mmol) of cyclo-
hexanone (22) afforded 0.960 g (83%) of 2331 as a colorless oil: 1H NMR
(CDCl3, 400 MHz)
d
1.71e1.86 (m,10H), 7.38 (d,1H, J¼7.6 Hz), 7.48 (t,1H,
J¼7.6 Hz), 7.63 (t, 1H, J¼7.6 Hz), 7.84 (d, 1H, J¼7.6 Hz); 13C NMR (CDCl3,
100 MHz)
d
22.3, 24.7, 36.4, 87.0, 121.0, 125.4, 125.8, 128.9, 133.9, 154.9,
d
1.47 (t, 3H, J¼7.3 Hz), 1.65 (s, 9H), 4.48 (q, 2H, J¼7.3 Hz), 7.34 (t, 1H,
170.1. Anal. Calcd for C13H14O2: C, 77.20; H, 6.98. Found: C, 76.91; H, 6.67.
J¼7.6 Hz), 7.37e7.50 (m, 2H), 8.10 (d, 1H, J¼8.3 Hz); 13C NMR (CDCl3,
100 MHz)
d 14.2, 27.9, 62.0, 72.1, 85.4, 115.1, 122.9, 123.9, 127.3,
4.4.7. 30H-Spiro[cyclopentane-1,10-isobenzofuran]-30-one
(25).
According to the general procedure B, treatment of 1.50
130.8, 132.6, 135.9, 148.3, 162.0. Anal. Calcd for C16H18INO4: C,
46.28; H, 4.37; N, 3.37. Found: C, 46.32; H, 4.53; N, 3.36.
g
(5.72 mmol) of methyl 2-iodobenzoate (12) with 4.85 mL
(6.30 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 0.530 g (6.30 mmol) of cyclohexanone (24) afforded
0.610 g (57%) of 2530 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
4.4.11. Di-tert-butyl 3-oxospiro[furo[3,4-b]indole-1,40-piperidine]-1,40-
dicarboxylate (32). According to general procedure B, treatment
of 1.00 g (2.41 mmol) of (31) with 2.41 mL (3.13 mmol) of a 1.3 M
d
1.97 (m, 2H), 2.11 (m, 6H), 7.39 (d, 1H, J¼7.6 Hz), 7.47 (t, 1H,
solution of i-PrMgCleLiCl followed by trapping with 0.48
(2.41 mmol) of ketone 7 gave 0.674 g (63%) of 32 as a colorless foam:
1H NMR (CDCl3, 400 MHz)
1.51 (s, 9H), 1.67 (s, 9H), 1.79 (m, 2H),
g
J¼7.6 Hz), 7.62 (t, 1H, J¼7.6 Hz), 7.83 (d, 1H, J¼7.6 Hz); 13C NMR
(CDCl3, 100 MHz)
d
24.9, 39.6, 95.5, 121.0, 125.3, 126.0, 128.8, 134.2,
d
152.6, 169.8. MS (C12H12O2): 189.3 (MþH).
2.24 (m, 2H), 3.31 (m, 2H), 4.21 (m, 2H), 7.34 (t,1H, J¼7.3 Hz), 7.54 (m,
2H), 8.36 (d, 1H, J¼8.3 Hz); 13C NMR (CDCl3, 100 MHz)
d 28.1, 28.4,
4.4.8. (ꢂ)-3-Phenyl-3-(trifluoromethyl)-2-benzofuran-1(3H)-one
(27). According to the general procedure B, treatment of 1.00 g
(3.82 mmol) of methyl 2-iodobenzoate (12) with 3.23 mL
(4.20 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 0.664 g (3.83 mmol) of 2,2,2-trifluoroacetophenone
(26) afforded 0.96 g (90%) of 27 as a colorless oil: 1H NMR (CDCl3,
35.4, 40.1, 80.0, 80.3, 85.5,117.3,120.3,120.8,124.0,127.6,128.7,142.8,
148.5, 148.7, 154.7, 159.3. Anal. Calcd for C24H30N2O6: C, 65.14; H,
6.83; N, 6.33. Found: C, 64.98; H, 6.73; N, 6.29.
4.4.12. 10-Benzyl-4-tert-butyl 3-oxospiro[furo[3,4-b]indole-1,40-piperi-
dine]-10,4(3H)-dicarboxylate (33). According to general procedure B,
treatment of 0.28 g (0.674 mmol) of (31) with 0.52 mL (0.674 mmol) of
a 1.3 M solution of i-PrMgCleLiCl followed by trapping with 0.157 g
400 MHz)
d
7.45 (m, 3H), 7.69 (t, 1H, J¼7.6 Hz), 7.78e7.85 (m, 3H),
7.93 (d, 1H, J¼7.6 Hz), 7.99 (d, 1H, J¼7.6 Hz); 13C NMR (CDCl3,

5256
J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
(0.674 mmol) of ketone 20 afforded 0.224 g (70%) of 33 as a colorless
foam: 1H NMR (CDCl3, 400 MHz)
1.72 (s, 9H), 1.83 (m, 2H), 2.27 (m,
methyl 2-iodobenzoate (12) with 4.85 mL (6.30 mmol) of a 1.3 M
solution of i-PrMgCleLiCl followed by trapping with 1.065 g
(5.72 mmol) of 2-bromopyridinecarboxaldehyde (44) afforded
1.50 g (90%) of 45 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d
2H), 3.41 (m, 2H), 4.31 (m, 2H), 5.22 (s, 2H), 7.37 (m, 6H), 7.53 (m, 2H),
8.38 (d,1H, J¼8.6Hz);13CNMR(CDCl3,100MHz)
d28.1, 35.3, 40.4, 67.4,
80.1, 85.6, 117.3, 120.2, 120.7, 124.0, 127.6, 128.1, 128.2, 128.6, 128.7,
136.6, 142.8, 148.3, 148.7, 155.2, 159.2. Anal. Calcd for C27H28N2O6: C,
68.05; H, 5.92; N, 5.88. Found: C, 67.81; H, 5.72; N, 5.79.
d
6.92 (s, 1H), 7.27 (dd, 1H, J¼7.7, 4.7 Hz), 7.42 (dd, 1H, J¼7.7, 1.9 Hz),
7.62 (m, 1H), 7.65e7.72 (m, 2H), 8.00 (d, 1H, J¼7.7 Hz), 8.41 (dd, 1H,
J¼4.7, 1.9 Hz); 13C NMR (CDCl3, 100 MHz)
d 79.9, 122.9, 123.4, 125.1,
130.0, 134.1, 134.8, 136.2, 141.9, 148.6, 150.5, 170.0; Anal. Calcd for
C13H8BrNO2: C, 53.82; H, 2.78; N, 4.83. Found: C, 53.68; H, 2.60; N,
4.69.
4.4.13. (ꢂ)-4-(3-Oxo-1,3-dihydro-2-benzofuran-1-yl)benzonitrile
(35). Method A: According to general procedure B, treatment of
1.50 g (5.72 mmol) of methyl 2-iodobenzoate (12) with 4.85 mL
(6.30 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 0.75 g (5.72 mmol) of 4-cyanobenzaldehyde (34)
afforded 1.22 g (91%) of 3533 as a colorless solid: 1H NMR (CDCl3,
4.4.18. (ꢂ)-6-Bromo-3-(4-bromophenyl)isobenzofuran-1(3H)-one
(48). According to general procedure B, treatment of 1.0
g
(2.93 mmol) of methyl 2-iodobenzoate (12) with 1.76 mL (3.52 mmol)
of a 1.3 M solution of i-PrMgCleLiCl followed by trapping with 0.570 g
(3.08 mmol) of aldehyde 47 afforded 0.750 g (70%) of 48 as a colorless
400 MHz)
d
6.46 (s, 1H), 7.36 (d, 1H, J¼7.6 Hz), 7.45 (d, 2H, J¼8.4 Hz),
7.58 (t, 1H, J¼7.6 Hz), 7.68 (m, 3H), 7.94 (d, 1H, J¼7.6 Hz); 13C NMR
(CDCl3, 100 MHz)
d
81.3, 113.1, 118.2, 122.7, 125.1, 126.0, 127.4, 129.9,
solid: 1H NMR (CDCl3, 400 MHz)
d
6.43 (s, 1H), 7.16 (d, 2H, J¼8.4 Hz),
7.22 (d, 1H, J¼8.1 Hz), 7.53 (d, 2H, J¼8.5 Hz), 7.79 (dd, 1H, J¼8.2,
1.8 Hz); 13C NMR (CDCl3, 100 MHz)
81.8, 123.7, 123.8, 124.4, 127.6,
132.9, 134.8, 141.7, 148.6, 170.0. Anal. Calcd for C15H9NO2$0.2H2O: C,
75.43; H, 3.97; N, 5.86. Found: C, 75.74; H, 3.57; N, 5.95.
d
Method B: According to general procedure B, treatment of 1.50 g
(6.55 mmol) of 4-iodobenzonitrile (36) with 5.04 mL (6.55 mmol)
of a 1.3 M solution of i-PrMgCleLiCl followed by trapping with
1.08 g (7.20 mmol) of methyl 2-formylbenzoate (37) afforded 0.99 g
(64%) of 35, which was identical to that prepared by Method A.
128.6, 128.8, 132.3, 134.8, 137.6, 147.8, 168.6; MS (C14H8Br2O2): 366.9
(MþHþ).
4.4.19. (ꢂ)-3-(But-3-en-1-yl)isobenzofuran-1(3H)-one (50). According
to general procedure B, treatment of 2.68 g (10.21 mmol) of methyl 2-
iodobenzoate (12) with 9.82 mL (12.77 mmol) of a 1.3 M solution of i-
PrMgCleLiCl followed by trapping with 1.20 g (14.30 mmol) of alde-
4.4.14. (ꢂ)-3-(1,3-Benzodioxol-5-yl)-2-benzofuran-1(3H)-one (34).
According to general procedure B, treatment of 1.5 g (5.72 mmol) of
methyl 2-iodobenzoate (12) with 4.85 mL (6.30 mmol) of a 1.3 M
solution of i-PrMgCleLiCl followed by trapping with 0.86 g
(5.72 mmol) of piperonal (38) afforded 1.29 g (89%) of 3934 as
1
hyde 49 afforded 1.83 g (95%) of 50 as a yellow oil: H NMR (CDCl3,
400 MHz) d 1.83e1.92 (m, 1H), 2.13e2.38 (m, 3 H), 5.05e5.14 (m, 2H),
5.53 (dd, 1H, J¼8.1, 3.5 Hz), 5.81e5.92 (m, 1H), 7.47 (d, 1H, J¼7.6 Hz),
7.56 (t, 1H, J¼7.5 Hz), 7.70 (t, 1H, J¼7.7 Hz), 7.93 (d, 1H, J¼7.6 Hz); 13C
a colorless solid: 1H NMR (CDCl3, 400 MHz)
d
5.98 (m, 2H), 6.34 (s,
NMR (CDCl3,100 MHz) d 29.1, 34.1, 80.6, 115.9, 121.8,125.7, 126.2,129.1,
1H), 6.61 (s,1H), 6.81 (d,1H, J¼7.9 Hz), 6.85 (d,1H, J¼7.9 Hz), 7.33 (d,
134.0, 136.8, 149.9, 170.5; Anal. Calcd for C12H12O2: C, 76.57; H, 6.43.
Found: C, 76.01; H, 6.23.
1H, J¼7.6 Hz), 7.56 (t,1H, J¼7.5 Hz), 7.68 (t,1H, J¼7.5 Hz), 7.97 (d,1H,
J¼7.6 Hz); 13C NMR (CDCl3,100 MHz)
d 82.7,101.4,107.3,108.4,121.5,
122.9,125.6,125.8,129.4,130.0,134.3,148.3,148.6,149.6,170.3. Anal.
Calcd for C15H10O4: C, 70.84; H, 3.96. Found: C, 70.44; H, 3.77.
4.4.20. (ꢂ)-3-Butyl-2-benzofuran-1(3H)-one (52). According to
general procedure B, treatment of 2.00 g (7.62 mmol) of methyl 2-
iodobenzoate (12) with 5.87 mL (7.63 mmol) of a 1.3 M solution of i-
PrMgCleLiCl followed by trapping with 0.986 g (11.45 mmol) of
valeraldehyde (51) afforded 1.19 g (82%) of 52 as a colorless oil: 1H
4.4.15. (ꢂ)-3-(4-Bromo-2-fluorophenyl)-2-benzofuran-1(3H)-one
(41). According to general procedure B, treatment of 1.5
g
(5.72 mmol) ofmethyl 2-iodobenzoate(12)with4.85mL(6.30 mmol)
of a 1.3 M solution of i-PrMgCleLiCl followed by trapping with 1.16 g
(5.72 mmol) of 4-bromo-2-fluorobenzaldehyde (40) afforded 1.35 g
NMR (CDCl3, 400 MHz)
d
0.88 (t, 3H, J¼7.1 Hz), 1.30e1.47 (m, 4H),
1.68e1.76 (m, 1H), 1.99e2.05 (m, 1H), 5.45 (m, 1H), 7.42 (d, 1H,
J¼7.6 Hz), 7.47 (t, 1H, J¼7.6 Hz), 7.65 (t, 1H, J¼7.6 Hz), 7.84 (d, 1H,
(77%) of 41 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d
6.70 (s,
J¼7.6 Hz); 13C NMR (CDCl3, 100 MHz)
d 13.8, 22.4, 26.8, 34.4, 81.4,
1H), 7.05 (t, 1H, J¼8.0 Hz), 7.30 (dd, 1H, J¼9.8, 1.9 Hz), 7.37 (dd, 1H,
121.8, 125.5, 126.1, 129.0, 134.0, 150.1, 170.6. MS (C12H14O2): 191.1
J¼9.8, 1.9 Hz), 7.45 (d, 1H, J¼7.6 Hz), 7.60 (t, 1H, J¼7.6 Hz), 7.69 (t, 1H,
(MþHþ).
J¼7.6 Hz), 7.98 (d, 1H, J¼7.6 Hz); 13C NMR (CDCl3, 100 MHz)
d 76.2,
119.7 (d, J¼24 Hz), 122.7 (d, J¼3.0 Hz),123.4 (d, J¼60 Hz),123.5,125.4,
4.4.21. (ꢂ)-3-(4-Bromophenyl)isobenzofuran-1(3H)-one (54). Accor-
ding to general procedure B, treatment of 1.2 g (5.24 mmol) of
iodonitrile (53) with 5.04 mL (6.55 mmol) of a 1.3 M solution of
i-PrMgCleLiCl followed by trapping with 1.26 g (6.81 mmol) of al-
dehyde 47 afforded 1.18 g (78%) of 5433 as a colorless solid: 1H NMR
125.9, 128.1 (d, J¼30 Hz), 128.8 (d, J¼3.0 Hz), 129.7, 134.7, 148.6,160.2
(d, J¼251.0 Hz), 170.0; 19F NMR (CDCl3, 376 MHz)
d
ꢀ115.7. Anal.
Calcd for C14H8BrFO2: C, 54.75; H, 2.63. Found: C, 54.66; H, 2.37.
4.4.16. (ꢂ)-3-(2-Bromo-6-chloro-3-fluorophenyl)isobenzofuran-
1(3H)-one (43). According to general procedure B, treatment of
0.40 g (1.53 mmol) of methyl 2-iodobenzoate (12) with 1.17 mL
(1.53 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed by
trapping with 0.362 g (1.53 mmol) of aldehyde 4235 afforded
0.427 g (82%) of 43 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
(CDCl3, 400 MHz)
d
6.37 (s, 1H), 7.17 (d, 2H, J¼8.4 Hz), 7.33 (d, 1H,
J¼7.6 Hz), 7.50 (d, 2H, J¼8.5 Hz), 7.57 (t, 1H, 7.5 Hz), 7.67 (t, 1H,
J¼7.4 Hz), 7.95 (d, 1H, J¼7.6 Hz); 13C NMR (CDCl3, 100 MHz)
d 81.9,
122.8,123.5,125.4,125.8, 128.6, 129.6,132.2,134.5,135.5,149.2,170.3;
MS (C14H10BrO2): 289.0 (MþHþ).
d
6.99 (s, 1H), 7.19 (dd, 1H, J¼8.7, 1.6 Hz), 7.34 (dd, 1H, J¼7.6, 0.6 Hz),
7.53e7.62 (m, 2H), 7.68 (dt, 1H, J¼7.5, 1.0 Hz), 8.01 (d, 1H, J¼7.6 Hz);
13C NMR (CDCl3, 100 MHz)
4.4.22. (ꢂ)-1-tert-Butyl 2-ethyl 3((4-cyanophenyl)(hydroxy)methyl)-
1H-indole-1,2-dicarboxylate (55). According to general procedure C,
treatment of 0.370 g (0.891 mmol) of 31 with 0.754 mL (0.98 mmol)
of a 1.3 M solution of i-PrMgCleLiCl followed by trapping with
0.117 g (0.891 mmol) of 4-cyanobenzaldehyde (34) afforded 0.338 g
d
76.1, 108.8 (d, J¼22 Hz), 122.0, 123.4 (d,
J¼20 Hz), 125.8, 126.1, 126.8 (d, J¼4 Hz), 129.7, 133.9 (d, J¼4 Hz),
134.4, 134.6, 147.5, 158.3 (d, J¼254 Hz), 170.1. Anal. Calcd for
C14H7BrClFO2: C, 49.23; H, 2.07. Found: C, 48.91; H, 1.79.
(90%) of 55 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.29 (t, 3H,
J¼7.2 Hz), 1.66 (s, 9H), 3.41 (d, 1H, J¼5.7 Hz), 4.34 (q, 2H, J¼7.2 Hz),
6.28 (d, 1H, J¼5.7 Hz), 7.22 (t, 1H, J¼7.1 Hz), 7.41 (t, 1H, J¼8.5 Hz),
7.54 (d, 1H, J¼7.1 Hz), 7.60 (d, 2H, J¼8.5 Hz), 7.64 (d, 2H, J¼8.5 Hz),
4.4.17. (ꢂ)-3-(2-Bromopyridin-3-yl)-2-benzofuran-1(3H)-one (44).
According to general procedure B, treatment of 1.5 g (5.72 mmol) of

J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
5257
8.06 (d, 1H, J¼8.5 Hz); 13C NMR (CDCl3, 100 MHz)
d
14.0, 28.0, 62.2,
magnesium sulfate and 150 mL of DCM. Sulfuric acid (1.40 mL,
26.3 mmol) was added in one portion and the reaction mixture was
stirred at room temperature for 30 min. Carboxylic acid 71 (7.00 g,
26.3 mmol) and tert-butanol (9.75 g, 132 mmol) were added in one
portion and the resulting reaction mixture was stirred at room
temperature overnight. The reaction mixture was then filtered and
the filtrate was carefully quenched with satd NaHCO3. The organic
layer was separated, washed with brine, dried over MgSO4, filtered,
and concentrated. The residue was purified by column chroma-
tography (EtOAc/hexanes) to give 8.3 g (98%) of 72 as a white solid:
67.6, 85.3, 111.1, 115.2, 118.8, 121.2, 123.5, 126.2, 126.7, 127.1, 127.6,
132.1, 136.4, 147.5, 149.1, 163.1. Anal. Calcd for C24H24N2O5: C, 68.56;
H, 5.75; N, 6.66. Found: C, 68.39; H, 5.67; N, 6.56.
4.4.23. (ꢂ)-7-(1,3-Benzodioxol-5-yl)-furo[3,4-b]pyridine-5(7H)-one
(57). According to general procedure C, treatment of 2.00 g
(7.22 mmol) of ethyl 2-iodopyridine-3-carboxylate (28) with
6.11 mL (7.94 mmol) of a 1.3 M solution of i-PrMgCleLiCl followed
by trapping with 1.19 g (7.94 mmol) of piperonal (38) afforded
1.52 g (83%) of 57 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
1H NMR (CDCl3, 400 MHz)
d 1.65 (s, 9H), 7.05e7.13 (m, 2H), 7.63 (d,
d
5.98 (m, 2H), 6.37 (9s, 1H), 6.75 (d, 1H, J¼1.5 Hz), 6.84 (d, 1H,
1H, J¼8.6 Hz); 13C NMR (CDCl3, 100 MHz)
d 28.1, 83.9, 92.1 (d,
J¼8.0 Hz), 6.96 (dd, 1H, J¼8.0, 1.5 Hz), 7.52 (dd, 1H, J¼7.7, 4.8 Hz),
J¼2.9 Hz), 115.7 (d, J¼21.5 Hz), 129.9 (d, J¼20.2 Hz), 131.6 (d,
J¼8.1 Hz), 134.9 (d, J¼3.6 Hz), 158.8 (d, J¼253.9 Hz), 164.0. Anal.
Calcd for C11H12FIO2: C, 41.02; H, 3.75. Found: C, 41.10; H, 3.52.
8.27 (dd, 1H, J¼7.7, 1.6 Hz), 8.89 (dd, 1H, J¼4.9, 1.5 Hz); 13C NMR
(CDCl3, 100 MHz) d 83.0, 101.4, 107.1, 108.6, 119.5, 121.3, 124.3, 128.2,
134.2, 148.2, 148.6, 155.7, 168.3. Anal. Calcd for C14H9NO4: C, 65.88;
H, 3.55; N, 5.49. Found: C, 65.48; H, 3.28; N, 5.33.
4.4.29. tert-Butyl 2-(tert-butoxy)-6-iodobenzoate (73). A 200-mL
round-bottomed flask was charged with iodoester 72 (4.0 g,
12.42 mmol) and 50 mL of THF. The reaction mixture was cooled at
5 ꢁC and potassium tert-butoxide (1.53 g, 13.66 mmol) was added in
one portion. The resulting reaction mixture was stirred at room
temperature for 17 h and then cooled to room temperature and
quenched with satd NH4Cl. The aqueous layer was separated and
extracted with EtOAc. The organic layer was washed with brine,
dried over MgSO4, filtered, and concentrated to give 4.1 g (88%) of
4.4.24. (ꢂ)-7-(4-Bromophenyl)furo[3,4-b]pyridin-5(7H)-one
(58). According to general procedure C, treatment of 1.4
g
(5.05 mmol) of 2-iodopyridine (28) with 5.25 mL (6.82 mmol) of
a 1.3 M solution of i-PrMgCleLiCl followed by trapping with 1.22 g
(6.52 mmol) of aldehyde 47 afforded 1.02 g (70%) of 58 as a colorless
solid: 1H NMR (CDCl3, 400 MHz)
d
6.41 (s,1H), 7.34 (d, 2H, J¼8.4 Hz),
7.53 (d, 3H, J¼8.6 Hz), 8.26 (d, 1H, J¼7.8 Hz), 8.87 (s, 1 H); 13C NMR
(CDCl3, 100 MHz)
d
82.0, 119.1, 123.4, 124.4, 128.2, 132.1, 133.8, 134.3,
73 as a colorless oil: 1H NMR (CDCl3, 400 MHz)
d 1.45 (s, 9H), 1.65 (s,
155.8, 168.0, 168.1; MS (C13H8BrNO2): 290.0 (MþHþ).
9H), 6.96 (t, 1H, J¼8.2 Hz), 7.11 (d, 1H, J¼8.3 Hz), 7.45 (d, 1H,
J¼7.9 Hz). Anal. Calcd for C15H21IO3: C, 47.89; H, 5.63. Found: C,
47.95; H, 5.44.
4.4.25. (ꢂ)-4-(5-Oxo-5,7-dihydrofuro[3,4-b]pyridin-7-yl)benzoni-
trile (59). According to general procedure C, treatment of 1.00 g
(3.61 mmol) of ethyl 2-iodopyridine (28) with 3.33 mL (4.33 mmol)
of a 1.3 M solution of i-PrMgCleLiCl followed by trapping with
0.473 g (3.61 mmol) of 4-cyanobenzaldehyde (34) afforded 0.600 g
4.4.30. Methyl 2-hydroxy-6-iodobenzoate (74). A 100-mL round-
bottomed flask was charged with ester 73 (1.73 g, 4.60 mmol)
and 20 mL of DCM at 5 ꢁC. TFA (0.71 mL, 9.20 mmol) was added
drop wise via syringe and the resulting reaction mixture was slowly
warmed to room temperature over 1 h. The reaction mixture was
then diluted with water. The organic layer was separated, washed
with brine, and concentrated to give 1.3 g of a white solid. The solid
was dissolved in 15 mL of DCM and charged with oxalyl chloride
(0.60 mL, 6.90 mmol) and cat. DMF. The reaction mixture was
stirred at room temperature for 1 h and then quenched with excess
MeOH. Water was then added to the reaction mixture. The organic
layer was separated, washed with brine, and concentrated. The
residue was purified by column chromatography (EtOAc/hexanes)
to give 1.15 g (90%) of 74 as a white solid: 1H NMR (CDCl3, 400 MHz)
(70%) of 59 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d 6.49 (s,
1H), 7.54 (dd, 1H, J¼7.9, 4.9 Hz), 7.66 (d, 2H, J¼8.5 Hz), 7.70 (d, 2H,
J¼8.5 Hz), 8.26 (dd,1H, J¼7.9,1.6 Hz), 8.86 (dd,1H, J¼4.9,1.6 Hz); 13C
NMR (CDCl3, 100 MHz)
d 81.1, 113.0, 118.2, 119.0, 124.7, 127.0, 132.6,
134.5, 139.9, 155.9, 167.3, 167.8. Anal. Calcd for C14H8N2O2: C, 71.18;
H, 3.41; N, 11.86. Found: C, 70.99; H, 3.34; H, 11.59.
4.4.26. (ꢂ)-7-(2-Methoxy-5,6,7,8-tetrahydroquinolin-3-yl)furo[3,4-
b]pyridin-5(7H)-one (61). According to general procedure C, treat-
ment of 0.25 g (0.90 mmol) of ethyl 2-iodopyridine (28) with
0.833 mL (1.08 mmol)ofa 1.3Msolution ofi-PrMgCleLiClfollowedby
trapping with 0.173 g (0.90 mmol) of aldehyde 6036 afforded 0.180 g
d
4.00 (s, 3H), 6.97e7.04 (m, 2H), 7.61 (dd, 1H, J¼7.2, 1.6 Hz) 10.83 (s,
(67%) of 61 as a colorless solid: 1H NMR (CDCl3, 400 MHz)
d
1.72e1.84
1H); 13C NMR (CDCl3, 100 MHz)
d
52.0, 93.8, 116.8, 118.2, 133.9,
(m, 4H), 2.62 (t, 2H, J¼6.3 Hz), 2.76 (t, 2H, J¼6.3 Hz), 3.75 (s, 3H), 6.51
135.1, 162.4, 169.0. Anal. Calcd for C8H7IO3: C, 34.56; H, 2.54. Found:
C, 34.63; H, 2.16.
(s, 1H), 7.11 (s, 1H), 7.47 (dd, 1H, J¼7.7, 4.7 Hz), 8.24 (dd, 1H, J¼7.7,
1.4 Hz), 8.82 (dd, 1H, J¼4.7, 1.4 Hz); 13C NMR (CDCl3, 100 MHz)
d 22.7,
22.9, 27.6, 32.2, 53.3, 80.1,113.8,120.5,123.9,124.7,133.8,139.5,155.2,
156.3,159.4,168.5,168.7. Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44;
N, 9.45. Found: C, 68.92; H, 5.41; H, 9.46.
4.4.31. (ꢂ)-Chrycolide (70). A 40-mL vial equipped with a nitrogen
inlet needle and thermocouple was charged with iodide 74
(0.222 g, 0.798 mmol) and 3 mL of THF. The reaction mixture was
cooled at 5 ꢁC while sodium hydride (0.038 g, 0.96 mmol) was
added in three portions. The resulting reaction mixture was stirred
at 5 ꢁC for 10 min and then cooled to ꢀ70 ꢁC. A 1.3 M solution of
i-PrMgCleLiCl (0.921 mL, 1.20 mmol) was added drop wise via sy-
ringe over 3 min and the reaction mixture was stirred at ꢀ70 ꢁC for
30 min. Thiophene-2-carbaldehyde (65) (0.224 g, 1.80 mmol) was
added in one portion. The resulting reaction mixture was warmed
to room temperature over 1 h and then quenched with satd NH4Cl.
The aqueous layer was separated and extracted with EtOAc. The
combined organic layers were washed with brine, dried over
MgSO4, filtered, and concentrated onto silica gel. The residue was
purified by column chromatography (EtOAc/hexanes) to give
0.185 g (92%) of 70 as a white solid: 1H NMR (CDCl3, 400 MHz)
4.4.27. (ꢂ)-7-Ethylfuro[3,4-b]pyridin-5(7H)-one (63). According to
general procedure C, treatment of 4.10 g (14.80 mmol) of 2-
iodopyridine (28) with 14.23 mL (18.50 mmol) of a 1.3 M solution
of i-PrMgCleLiCl followed by trapping with 1.12 g (19.24 mmol) of
aldehyde 62 afforded 1.45 g (60%) of 63 as a colorless oil: 1H NMR
(CDCl3, 400 MHz)
d
1.02 (t, 3H, J¼7.4 Hz), 1.91e1.99 (m, 2H),
2.25e2.32 (m, 1H), 5.47 (dd, 1H, J¼6.9, 4.4 Hz), 7.50 (dd, 1H, J¼7.7,
4.9 Hz), 8.21 (d, 1H, J¼7.7 Hz), 8.88 (s, 1H); 13C NMR (CDCl3,
100 MHz) d 8.7, 26.2, 83.2, 120.2, 124.0, 134.0, 155.1, 168.7, 168.9; MS
(C9H9NO2): 164.0 (MþHþ).
4.4.28. tert-Butyl 2-fluoro-6-iodobenzoate (72). A 500-mL round-
bottomed flask was charged with 12.7
g
(105 mmol) of
d 6.71 (s, 1H), 6.98e7.06 (m, 3H), 7.19 (s, 1H), 7.42 (s, 1H), 7.62

5258
J.T. Kuethe, K.M. Maloney / Tetrahedron 69 (2013) 5248e5258
(t, 1H, J¼6.2 Hz), 7.84 (s, 1H); 13C NMR (CDCl3, 100 MHz)
d 79.1, 111.1,
Takiyama, N. Tetrahedron Lett. 1984, 25, 4233e4236; (b) Imamoto, T.; Takiyama,
N.; Nakamura, K. Tetrahedron Lett. 1985, 26, 4763e4766; (c) Imamoto, T.;
Sugiyura, Y.; Takiyama, N.; Hatojima, T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111,
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45, 497e500.
114.6, 116.2, 127.1, 127.9, 128.3, 137.2, 138.2, 148.7, 156.5, 171.3. MS
(C12H8O3S): 233.0 (MþHþ).
16. Adams, N. D.; Chaudhari, A. M.; Kiesow, T. J.; Parrish, C. A.; Reif, A. J.; Ridgers, L.
H.; Schmidt, S. J.; Wiggal, K. Patent WO2006065652 A1.
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