Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive Heteroaromatic Enones

Article abstract of DOI:10.1021/acs.joc.7b03171

Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophene-yl, and 2-benzothiophene-yl) have traditionally proven difficult or impossible to cyclize with typical Br?nsted and Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with typical UV exposure times of 3.4-6.8 min. In all cases, 2-furyl and 2-thiophene-yl enones cyclized, whereas 2-benzofuryl and 2-benzothiophene-yl enones exhibited divergent properties with reactivity patterns tied to the identity of the vinyl group. This report discloses the first photo-Nazarov reactions of tetrahydropyridine-substituted 2-furyl ketones, providing a direct approach to the corresponding fused heterocyclic motifs built around a central cyclopentanone. These motifs constitute the core structures of biologically active natural products, including the marine alkaloid nakadomarin A.

Full text of DOI:10.1021/acs.joc.7b03171

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Featured Article
Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing
a Class of Traditionally Unreactive Heteroaromatic Enones
William L. Ashley, Evan L. Timpy, and Thomas Charles Coombs
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b03171 • Publication Date (Web): 05 Feb 2018
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Flow Photo-Nazarov Reactions of 2-Furyl Vinyl Ketones: Cyclizing a Class of Traditionally Unreactive
Heteroaromatic Enones
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William L. Ashley, Evan L. Timpy, and Thomas C. Coombs*
Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Dobo Hall,
Wilmington, NC 28403, USA
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*Corresponding author. Tel.: +1 910 962 7250; fax: +1 910 962 3013.
E-mail address: coombst@uncw.edu (T.C. Coombs).
ABSTRACT: Nazarov reactions of 2-furyl vinyl ketones and related heteroaromatic enones, to produce
furan-fused cyclopentanones using a flow photochemical approach, are described. Compounds
possessing this connectivity between heterocycle and ketone (2-furyl, 2-benzofuryl, 2-thiophenyl, and 2-
benzothiophenyl) have traditionally proven difficult or impossible to cyclize with typical Brønsted and
Lewis acid mediated methods. Using mild flow photochemistry conditions and acetic acid (AcOH) or
hexafluoroisopropanol (HFIP) as solvent, these compounds were found to cyclize in 45-97% yields, with
typical UV exposure times of 3.4-6.8 minutes. In all cases, 2-furyl and 2-thiophenyl enones cyclized,
whereas 2-benzofuryl and 2-benzothiophenyl enones exhibited divergent properties with reactivity
patterns tied to the identity of the vinyl group. This report discloses the first photo-Nazarov reactions of
tetrahydropyridine-substituted 2-furyl ketones, providing a direct approach to the corresponding fused
heterocyclic motifs built around a central cyclopentanone. These motifs constitute the core structures
of biologically-active natural products, including the marine alkaloid nakadomarin A.
INTRODUCTION
The Nazarov reaction of heteroaryl vinyl ketones offers direct access to heterocycle-fused
cyclopentanones, substructures common to many biologically-active small molecules.1 Concise
synthetic routes to the ketone substrates, predictable stereo- and regioselectivity in the cyclization, and
the versatility of the cyclopentenone products for subsequent transformation, render the aromatic
Nazarov reaction a powerful synthetic tool, despite the attenuated reactivity of aryl vinyl ketones
compared to other Nazarov substrates.2 Natural products, including bruceolline E,3 rocaglamide,4 and
merrilactone A,5 have been constructed using the heteroaromatic Nazarov reaction as a key strategic
step, employing heteroaryl vinyl ketones in which the heterocycles are connected via the 3-position to
the carbonyl. The reaction works especially well for substrates having this connectivity;6 however, the
situation is more complicated for those in which the heterocycle is joined through the 2-position to the
carbonyl: 2-pyrrolyl7 and 2-indolyl8 enones readily cyclize, whereas 2-thiophenyl6,
and 2-
9
benzothiophenyl8d, 9f, 10 enones often afford low product yields or exhibit a complete lack of reactivity
(Scheme 1, Eq. 1). Enones substituted with 2-furyl and 2-benzofuryl rings fail to cyclize altogether when
subjected to typical Nazarov conditions using Brønsted or Lewis acids.6, 9a, 11 Exceptions to this general
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observation are rare12, 13, 14 with Flynn15 and West16 reporting the useful finding that some 2-furyl-
substituted enones may be induced to cyclize using strong Brønsted acids through the introduction of an
activating oxazolidinone substituent alpha to the carbonyl on the vinyl group. The characteristic
reluctance of 2-furyl enones to undergo Nazarov cyclization is so pronounced that Frontier and
Eisenberg have exploited this property and developed an entirely different cyclization pathway for these
compounds in which a transition metal-mediated 1,2-hydride shift/intramolecular Friedel-Crafts
alkylation sequence affords furan-fused cyclohexanones (Scheme 1, Eq. 2).11a, 17
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Photochemical activation of aryl/heteroaryl vinyl ketones using UV light offers an alternative
means of achieving aromatic Nazarov cyclization, under milder conditions than those usually employed
with Lewis or Brønsted acid catalysis. Smith and Agosta’s 1973 disclosure that simple aryl vinyl ketones
undergo photo-Nazarov cyclization,18 and subsequent mechanistic studies by Leitich and co-workers in
199119 and 200120 using 1-cyclohexenyl phenyl ketone, laid the groundwork for this important
transformation. In 2009 and 2010, Chen and co-workers reported the first examples of the photo-
Nazarov reaction in total synthesis, cyclizing substituted phenyl vinyl ketones as key steps in their
approaches to the marine homosteroids nakiterpiosin21 and nakiterpiosinone.22 In 2010, Giannis also
disclosed the synthesis of terpendole E analogues via photo-Nazarov reactions of 3-indolyl vinyl
ketones.23 A study of the reaction scope by Gao and co-workers finally appeared in 2014, demonstrating
the range of substituted benzenes and heteroaromatics compatible with the transformation, including
3-thiophenyl and 3-benzothiophenyl vinyl ketones.24 A total synthesis of gracilamine from this group
soon followed.25 However, among these photo-Nazarov disclosures, 2-furyl-substituted and 2-
thiophenyl-substituted vinyl ketones remained conspicuously absent, leaving their viability in the
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reaction unknown. This gap is noteworthy given that a number of biologically-active natural products,
including the marine alkaloid nakadomarin A,26 Stemona alkaloids such as sessilifoliamide I,27 and the
homoisoflavonoid brazilide A,28 are characterized by core structures derived from furan-fused
cyclopentanones (Figure 1). Nakadomarin A, itself, has been the target of at least nine total syntheses,29
two formal syntheses,30 and numerous approaches to its polycyclic core,31 none of which utilize a
Nazarov reaction of a furan.32, 33 If photo-Nazarov cyclization of 2-furyl vinyl ketones such as 1 (Figure 1)
could be achieved, these natural products and similar compounds could be targeted using this
transformation.
This report describes our investigation into these substrate classes (Scheme 1, Eq. 3) using flow
photochemistry,34 and also describes the outcomes observed when tetrahydropyridines are
incorporated in the aryl vinyl ketone substrates. A flow photochemical approach was chosen at the
outset for the advantages it offers over traditional batch reactions run in immersion well reactors.
Uniform irradiation of the solution over shorter path lengths minimizes both the shielding effects of high
concentration and side reactions due to overexposure.34 Furthermore, anticipating the need for gram-
scale quantities of the Nazarov products for future applications, it was recognized that scaling out,
simply flowing larger volumes of solution at the same concentration under the same conditions, could
be used, avoiding the iterative optimization often required of batch reaction scale-up.
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RESULTS AND DISCUSSION
Synthesis of the requisite aryl vinyl ketones needed to begin the investigation was carried out as shown
in Table 1. Addition of lithiated heterocycles to -unsaturated aldehydes (2-4) was followed by
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oxidation of the resulting allylic alcohols using IBX in DMF.35 Good-to-excellent yields of the aryl vinyl
ketones (5-7) were generally obtained. DMP and PCC produced inferior results in the oxidation step,
affording low yields of product mixtures.
Cyclization of ketone 5a was investigated first, using a simple flow photochemical apparatus
adapted from the report by Booker-Milburn.36 The setup consisted of fluorinated ethylene propylene
(FEP) tubing (1.6 mm ID, 3.2 mm OD, 3.0 m length) wrapped around a double-walled borosilicate glass
immersion well housing a medium pressure mercury vapor immersion lamp (Figure 2).37 Ice-cooled
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Table 1. Aryl vinyl ketone synthesis
Entry Aldehyde
X
n
1
1
1
1
1
1
1
2
2
2
1
1
1
1
1
Ar-Li Prod Yield (%)
1
2
2
2
2
2
2
2
2
3
3
3
4
4
4
4
4
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
CH2
O
a
b
c
d
e
f
g
a
b
c
a
b
c
5a
5b
5c
5d
5e
5f
5g
6a
6b
6c
7a
7b
7c
7d
7g
75
90
91
67
79
39
68
72
79
77
60
68
78
83
54
3
4
5
6
7
8
9
10
11
12
13
14
15
Ar-Li =
O
O
O
O
d
g
water was flowed through the immersion well, and the solution of ketone was pumped through the FEP
tubing at specified concentrations and flow rates using a syringe pump. An initial survey of solvents was
conducted with 0.056 M solutions and a total exposure time of 3.4 minutes (flow rate = 1.8 mL/min)
(Table 2). Gratifyingly, the desired photo-Nazarov product (8) was formed. Low yields (16-20%) were
obtained in MeCN and 1,2-DCE, though 5a was completely consumed (entries 1 and 3). Both solvents
have been used in other photo-Nazarov applications.21-24 Adding acetic acid (5.0 equivalents) to each
solvent improved the yield of 8 (34-56%), though the effect was most pronounced in 1,2-DCE (entries 2
and 4). Starting material was again completely consumed. In the presence of acetic acid, the
production of a complex mixture of polar byproducts is suppressed. Under the same conditions,
trifluoroacetic acid produced 8 in 33% yield, but a significant quantity of unreacted starting material
(40%) remained (entry 5). In glacial acetic acid,19 the reaction went to completion, affording 72% of the
desired cyclopentenone (entry 6). Doubling the exposure time to 6.8 minutes (flow rate = 0.9 mL/min)
improved the yield to 86% (entry 8). Other variations in both concentration and exposure time
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produced inferior results (entries 9-13). Hexafluoroisopropanol (HFIP)38 was later discovered to be a
particularly suitable solvent for photo-Nazarov reactions of tetrahydropyran-substituted aryl vinyl
ketones, and while this solvent provided good results with compound 5a (Table 2, entries 14-16), the
results obtained in AcOH were generally superior. Control experiments in which 5a was refluxed in the
absence of UV irradiation, in either acetic acid or HFIP, failed to produce 8 after 48 hours. In acetic acid,
starting material was recovered (62%) and the formation of an allylic oxidation product, 2-(furan-2-
carbonyl)cyclohex-2-en-1-one, was observed (19%, entry 7), presumably the result of exposure to
adventitious atmospheric oxygen. In HFIP, unreacted starting material was quantitatively recovered
(entry 17).
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Figure 2. Flow photochemistry setup with syringe pump
Table 2. Photo-Nazarov optimization
Entry
Solvent
Concentration
(M)
Exposure Time
Yield (%)
1
2
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9
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13
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15
MeCN
MeCN/AcOHa
1,2-DCE
1,2-DCE/AcOHa
CF3CO2H
AcOH
0.056
0.056
0.056
0.056
0.056
0.056
0.056
0.056
0.056
0.028
0.028
0.028
0.112
0.056
0.028
3.4 min
3.4 min
3.4 min
3.4 min
3.4 min
3.4 min
reflux, 48 hd
6.8 min
2.3 min
3.4 min
17 min
16
34b
20
56
33 (40)c
72
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
HFIP
0 (62)c,e
86
52
68
65
43
34 min
3.4 min
3.4 min
3.4 min
49
55 (32)c
76 (5)c
HFIP
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HFIP
HFIP
0.014
0.056
3.4 min
74
reflux, 48 hd
0 (100)c
a5.0 equiv of AcOH added to solvent. bContains small impurity. cNumber in parentheses indicates recovered starting material. dReaction mixture
e
was refluxed 48 h in the absence of UV light. Allylic oxidation byproduct, 2-(furan-2-carbonyl)cyclohex-2-en-1-one, also recovered (19%).
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Following the initial survey of solvents and conditions for cyclization of 5a, an expanded study of
the furan- and thiophene-containing cyclohexenyl aryl vinyl ketones from Table 1 was initiated. It was
soon determined that one set of reaction conditions was not optimal for all substrates. Therefore, a
series of flow conditions was evaluated for each heteroaryl vinyl ketone, varying concentration and UV
exposure time using AcOH as solvent. All substrates investigated underwent successful photo-Nazarov
cyclization, and the best results for each compound are provided in Table 3.39 Importantly, the results of
this study demonstrated that substitution at both the 4-postion and 5-position of the furan was
tolerated, as evidenced by the cyclization of substrates bearing 5-methylfuran; 4,5-dimethylfuran; and
benzofuran heteroaromatics, to produce 9-11 (51-68%). Substrates bearing 2-thiophenyl and 2-
benzothiophenyl groups also cyclized in good yields, affording 13-14 (62-70%). The 3-furylketone isomer
delivered the highest yield among the cyclohexenyl substrates, producing 91% of 12. As noted in Table
2, hexafluoroisopropanol (HFIP) was also a suitable solvent for the photo-Nazarov reaction, but superior
results were obtained using AcOH for both cyclohexenyl substrates 5a and 5b (producing 8 and 13,
respectively).39 The results with cycloheptenyl ketones in HFIP were very different, with good-to-
excellent yields obtained for furan-, benzofuran-, and thiophene-substituted compounds (15-17, Table
3). The cis configurations of the ring-fused cyclopentanone products were confirmed by comparison of
NMR coupling constants and distinctive chemical shifts for the ring-junction hydrogens to data reported
for similar compounds synthesized via photo-Nazarov reaction, whose structures were confirmed by X-
ray crystallography.24,40
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Table 3. Photo-Nazarov reactions of 2-furyl and 2-thiophenyl enonesa,b
aNumbers in parentheses indicate recovered starting material. b3.4 min exposure time corresponds to a flow rate
c
of 1.8 mL/min; 6.8 min exposure time corresponds to a flow rate of 0.9 mL/min. dr = 20:1
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The prevalence of 6-membered heterocycles in natural products and compounds of
pharmaceutical importance prompted us to next evaluate a series of dihydropyranyl and
tetrahydropyridyl aryl vinyl ketones substituted with furans and thiophenes. Aryl vinyl ketones derived
from dihydropyranyl aldehyde 4 were synthesized as shown in Table 1. The remaining heterocyclic
substrates were made by routes involving Stille cross-coupling reactions of acid chlorides and vinyl or
aryl stannanes.41 Vinyl stannane synthesis was carried out as shown in Scheme 2.42 Addition of Bu3SnLi
(3.0 equiv), generated in situ from LDA and Bu3SnH, to tetrahydro-4H-pyran-4-one, followed by
treatment of the intermediate alkoxide with MsCl (4.0 equiv) and Et3N (7.5 equiv), led smoothly to the
desired vinyl stannane 18 in 50% yield. However, using N-Boc and N-Ts protected 4-piperidone, three
separate additions of MsCl (4.0 equiv) and Et3N (7.5 equiv), at 4-hour intervals, were required to drive
the intermediate alkoxides to vinyl stannane products (19 and 20). With vinyl stannanes in hand, Stille
couplings were carried out using the appropriate acid chlorides, producing aryl vinyl ketones 21-25. The
conditions used to synthesize each ketone are shown in Table 4.
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Scheme 2. Aryl vinyl ketone synthesis
Table 4. Stille coupling conditions for aryl vinyl ketone synthesis
Entry Stannane
X
O
O
O
NBoc
NTs
Ar =
2-furyla
Temp (°C)
115
170 (w)
170 (w)
125 (w)
90
Time
18 hrs
35 mins
35 mins
20 mins
30 mins
Prod Yield (%)
1
2
3
4
5
18
18
18
19
20
21
22
23
24
25
86
77
55
70
70
2-thiophenylb
2-benzofurylb
2-furylc
2-furylc
a2-Furoyl chloride limiting (1.0 equiv), with 18 (1.1 equiv) and Pd(PPh3)2Cl2 (0.025equiv). bAcyl chloride used in excess (1.1 equiv).
c2-Furoyl chloride used in excess (1.5 equiv).
Synthesis of the isomeric N-Boc and N-Ts protected tetrahydropyridyl aryl vinyl ketones leading
to the fused tricyclic core of nakadomarin A was conducted according to Scheme 3. Conversion of 26
and 27, obtained from 1,2,5,6-tetrahydropyridine-3-carboxylic acid hydrochloride, to the corresponding
acid chlorides was carried out using (COCl)2 in CH2Cl2. Following solvent exchange, Stille coupling with 2-
(tributylstannyl)furan afforded ketones 28 and 29.41
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Scheme 3. Synthesis of aryl vinyl ketones via Stille coupling
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With routes to the necessary heterocyclic aryl vinyl ketones developed, cyclization of
dihydropyranyl ketone 7a (Table 1) was undertaken, and the results are shown in Table 5. In contrast to
the outcomes obtained with carbocyclic analogs 5a and 6a, an unexpected interrupted Nazarov
cyclization occurred in HOAc, affording 30 as the major product. Prior studies of interrupted Nazarov
reactions suggest compound 30 results from nucleophilic attack of AcOH on the convex face of the
oxyallyl intermediate (45, Scheme 4) formed upon ring closure.43 Only small quantities of the desired
fused furan 31 (< 10%) were isolated. No reaction occurred when 7a was irradiated in CF3CO2H.
Gratifyingly, the expected Nazarov product (31) was formed in good yields using HFIP, though some
unreacted starting material was recovered under most conditions.39 Interestingly, using AcOH as
solvent, no interrupted Nazarov products were obtained for analogs of 7a in which the 2-furyl group was
replaced by either a 2-thiophenyl (7b) or the isomeric 3-furyl (7g) group. Instead, the expected fused
furan compounds 32 and 38 were formed.
Continuing with HFIP as solvent, good yields of cyclized products were obtained for both series
of isomeric dihydropyranyl ketones substituted with 2-furyl (producing 31 and 35) and 2-thiophenyl
(producing 32 and 36) groups. However, the corresponding benzofuran- and benzothiophene-
substituted compounds failed to cyclize in both series, using either HFIP or AcOH. This contrasts with
the results obtained for the corresponding carbocyclic substrates, which afforded the expected
benzofuran- and benzothiophene-fused cyclopentanones 11, 14 and 16 in good yields (Table 3). The
isomeric 3-furyl ketone again cyclized in highest yield with this series, affording 76% of 38. Both Ts- and
Boc-protected 4-furoyl-substituted 1,2,3,6-tetrahydropyridine substrates (24 and 25, Table 4)
underwent cyclization, affording 39 and 40.
The isomeric 3-furoyl-substituted 1,2,5,6-
tetrahydropyridines (28 and 29, Scheme 3) also cyclized, affording 41 and 42, the tricyclic structures
found at the core of nakadomarin A. However, significant quantities of unreacted starting materials (10-
43%) were usually recovered under the full range of concentrations and UV exposure times evaluated as
part of the standard survey. Notably, while maintaining a consistent 3.4-minute exposure time, a clear
correlation between concentration and yield emerged, with the best results (45-58% yields) typically
obtained under the most dilute conditions.39
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Table 5. Photo-Nazarov reactions of heterocyclic aryl vinyl ketonesa,b
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
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aNumbers in parentheses indicate recovered starting material. b2.3 min exposure time corresponds
to a flow rate of 2.7 mL/min; 3.4 min exposure time corresponds to a flow rate of 1.8 mL/min;
c
6.8 min exposure time corresponds to a flow rate of 0.9 mL/min. Reaction conducted in AcOH.
Stereochemical assignment assumes attack of AcOH on convex face of 45 (Scheme 4). dRecovered
starting material contains impurities. eWith 0.056M AcOH, 3.4 mins: 43% yield. fAll unreacted starting
material. gWith 0.056M AcOH, 3.4 mins: 58% yield.
Mechanistically, prior studies have concluded that photo-Nazarov reactions likely occur by
photo-mediated E-to-Z isomerization of the cyclic olefin, creating a strained ground state intermediate
which undergoes thermal conrotatory cyclization (Scheme 4).19,44 Orbital symmetry considerations45 for
both this pathway and that involving disrotatory ring closure of a photo-excited state lead to the same
stereochemical outcomes in the formation of the oxyallyl intermediate (45 in Scheme 4), so this aspect
of the reaction does not provide mechanistic insight. Indirect support for the Scheme 4 pathway
includes the observation that 6- or 7-membered cyclic olefins are required as the vinyl component of the
aryl vinyl ketone. Aryl vinyl ketones containing 5- and 8-membered carbocyclic olefins fail to cyclize,
apparently geometrically precluded from isomerizing or insufficiently strained to induce cyclization upon
isomerization.46 Furthermore, low-temperature NMR studies and trapping experiments involving photo-
initiated Nazarov reactions of medium-ring dienones44 and 1-cyclohexenyl phenyl ketone19 have
provided further evidence for the intermediacy of a strained ground state cyclic olefin cyclization
precursor (44 in Scheme 4).
The success of AcOH and HFIP as solvents for the photo-Nazarov reaction may relate, in part, to
acid- or hydrogen-bond-mediated acceleration of the cyclization (44 to 45). However, Leitich and co-
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workers have also found that the enol resulting from cyclization of 1-cyclohexenyl phenyl ketone (an
analog of 46) is readily oxidized by residual atmospheric oxygen in acetonitrile, producing the
corresponding -hydroxy ketone, which decomposes with further UV irradiation.19 When the reaction
was run in acetic acid, under an atmosphere of oxygen, this undesired oxidation was suppressed, likely
due to acid-catalyzed acceleration of the enol tautomerization to ketone.
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Scheme 4. Proposed photo-Nazarov cyclization mechanism
The photo-Nazarov requirement that the vinyl moiety be constrained within a ring should not be
seen as unduly restricting the utility of the method for applications in which the ring is not desired.
Cleavage of the pyran of tricycle 31 with BBr3, followed by treatment of the intermediate -
bromoketone with DBU, affords -unsaturated ketone 48 (Scheme 5). -Hydroxy ketone 49 is also
isolated as a minor product. The many transformations available to further elaborate both -
unsaturated ketones and primary alcohols should enable the synthesis of a variety of substituted
heterocycle-fused cyclopentanones.
Scheme 5. Pyran cleavage
Finally, a particularly attractive feature of flow chemistry is its ready scalability. With the goal of
producing sufficient quantities of tricyclic furan-fused cyclopentanone 8 for further applications, 1.50 g
of ketone 5a (0.056 M in glacial acetic acid) was subjected to continuous flow UV irradiation (Scheme 6).
Using our syringe pump setup (Figure 2), 152 mL of solution was flowed using 60-mL syringes and an
exposure time of 6.8 minutes. Irradiation of the entire volume under these conditions required just
under 3 hours (170 minutes), and delivered 1.33 g of product (89%), following aqueous work-up and
column chromatography.
Scheme 6. Scale-out of heteroaromatic photo-Nazarov reaction
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CONCLUSIONS
In summary, the viability of 2-furyl vinyl ketones as substrates for the photo-Nazarov cyclization has
been demonstrated, providing access to a range of tricyclic 2-furan-fused cyclopentanone structures not
generally accessible via other approaches to Nazarov cyclization. Substrates bearing 2-thiophenes were
found to be similarly viable. Cyclohexenyl, cycloheptenyl, dihydropyranyl, and tetrahydropyridyl
moieties were all suitable as cyclic vinyl groups, affording moderate to excellent yields of cyclization
products using the flow photochemistry conditions investigated. Notably, aryl vinyl ketones composed
of 2-benzofuran and 2-benzothiophene cyclized when carbocyclic olefin moieties were present, but did
not cyclize with dihydropyrans. Both AcOH and HFIP were generally useful solvents for the photo-
Nazarov reaction. This work demonstrates the first examples of photo-Nazarov cyclizations of aryl vinyl
ketones substituted with tetrahydropyridines, establishing the groundwork for further application to the
synthesis of alkaloids such as nakadomarin A, sessilifoliamide I, and related compounds.
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EXPERIMENTAL SECTION
General Information. Thin layer chromatography (TLC) was performed using glass plates coated
with silica gel (20 m thickness/10 m particle size) containing a fluorescent indicator (UV 254 nm).
Visualization was accomplished using UV light (254 nm) and/or basic potassium permanganate in water
with heating. Flash column chromatography was performed using silica gel (Dynamic Adsorbents: Flash
grade, 32‐63 μm, 60 Å, or Silicycle: SiliaFlash F60, 40-63 m, 230-400 mesh) with compressed air as a
source of positive pressure. Microwave reactions were run in sealed vials using a CEM Corporation
1
MARS 6 microwave synthesizer with an internal fiber optic probe. H and 13C (1H broad-band decoupled
1
mode) NMR spectra were recorded on a Bruker Avance (600 MHz H/150 MHz 13C) or a Bruker-300
1
Ultrashield NMR (300 MHz H/75 MHz 13C) with a SampleCaseTM operated using IconNMRTM and
TopSpinTM software. Chemical shifts are reported in parts per million (ppm) from tetramethylsilane and
referenced to the center line of the solvent: CDCl3 with CHCl3 as internal reference (7.26 ppm for 1H and
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77.23 ppm for C). Coupling constants are reported in Hertz (Hz). Infrared (IR) spectra were acquired
on a Nicolet 6700 FT-IR or a Nicolet iS5 FT-IR, and absorptions are reported in cm-1. Peaks are reported
with the following relative intensities: s (strong, 67-100%), m (medium, 40-67%), and w (weak, 20-40%),
and br (broad). High resolution mass spectra were obtained using an Agilent 1290 Infinity UHPLC with
Bruker Microtof-Q II high resolution mass spectrometer with a time of flight (TOF) mass analyzer and an
electrospray ion source (ESI). Photoreactions were conducted using a medium pressure mercury vapor
immersion lamp (450 W, 125-145 V, 3.6 A, 244.4 mm total length, 131.5 mm arc),37 supplied by Ace
Glass and purchased from VWR. Hexafluoroisopropanol (HFIP) was purchased from Oakwood Chemical,
1-cyclohexene-1-carboxaldehyde was purchased from Sigma-Aldrich, and 1,2,5,6-tetrahydro-3-
pyridinecarboxylic acid hydrochloride was purchased from ChemBridge Corporation.
Synthesis of heteroaryl vinyl ketones 5-7. Adapting literature procedures,24, 35 n-BuLi (1.6 M in
hexanes, 1.55 equiv) was added to a solution of heteroaromatic (1.50 equiv) in anhydrous
tetrahydrofuran (0.13 mol aldehyde/L) at 0 °C under argon. After addition of n-BuLi was complete, the
solution was warmed to room temperature and stirred. After 1 h, the solution was cooled to -78 °C in a
dry ice/acetone bath, and aldehyde (2-4, 1.00 equiv) was added dropwise. The solution continued to stir
at -78 °C for 1 h, and was then warmed to 0 °C and quenched with water (10 mL). The biphasic mixture
was transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted
with ethyl acetate (3 × 15 mL), and the combined organic layers were washed with brine (25 mL), dried
over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude secondary
alcohol. o-Iodoxybenzoic acid (IBX) (1.50 equiv) was added to a solution of the crude alcohol in
dimethylformamide (5 mL/mmol IBX), and the mixture was stirred at room temperature for 1 h. Water
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(10 mL) was added to the flask and stirring was continued for 5 min. Precipitated solids were filtered off
using a Buchner funnel, and the solids were rinsed with EtOAc (15 mL). The filtrate was transferred to a
separatory funnel and the layers were separated. The organic layer was washed with water (3 × 15 mL),
dried over magnesium sulfate, and concentrated under reduced pressure. The crude reaction mixture
was purified by silica gel column chromatography, affording ketones 5-7 (see details below for each
product). When 3-bromofuran was used as the heteroaromatic, the reaction was cooled to -78 °C
before addition of n-BuLi. The reaction was then stirred for 20 minutes at -78 °C before the aldehyde
was added.
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Cyclohex-1-en-1-yl(furan-2-yl)methanone,
(5a).
Prepared
from
1-cyclohexene-1-
carboxaldehyde (2) and furan. Purified via silica gel column chromatography using 10% EtOAc in
hexanes, affording a yellow oil (220 mg, 1.25 mmol, 75% yield). Spectroscopic data were consistent with
literature values.47
Cyclohex-1-en-1-yl(thiophen-2-yl)methanone, (5b). Prepared from 1-cyclohexene-1-
carboxaldehyde (2) and thiophene. Purified via silica gel column chromatography using 10% EtOAc in
hexanes, affording a yellow oil (346 mg, 1.80 mmol, 90% yield). Spectroscopic data were consistent with
literature values.47
Benzofuran-2-yl(cyclohex-1-en-1-yl)methanone, (5c).
Prepared from 1-cyclohexene-1-
carboxaldehyde (2) and 2,3-benzofuran. Purified via silica gel column chromatography using 10% EtOAc
in hexanes, affording a yellow solid (mp = 52-53 °C) (413 mg, 1.83 mmol, 91% yield). TLC: Rƒ = 0.52, (10%
EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.68 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 7.46-7.43
(m, 1H), 7.38 (d, J = 0.8 Hz, 1H), 7.31-7.28 (m, 1H), 7.12-7.10 (m, 1H), 2.46-2.43 (m, 2H), 2.36-2.33 (m,
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2H), 1.77-1.68 (m, 4H). C{1H} NMR (150 MHz, CDCl3): δ 185.7, 155.9, 152.5, 142.3, 138.8, 127.9, 127.1,
123.9, 123.2, 114.7, 112.6, 26.4, 24.2, 22.1, 21.8. IR (cm-1): 2933 (m), 1636 (s). HRMS: Calculated for
C15H14NaO2 ([M+Na]+): 249.0886. Found: 249.0893.
Benzo[b]thiophen-2-yl(cyclohex-1-en-1-yl)methanone, (5d). Prepared from 1-cyclohexene-1-
carboxaldehyde (2) and benzo[b]thiophene. Purified via silica gel column chromatography using 10%
EtOAc in hexanes, affording a yellow solid (mp = 82-83 °C) (252 mg, 1.04 mmol, 67% yield). TLC: Rƒ =
0.34, (10% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 8.2 Hz, 2H), 7.80 (s, 1H), 7.44 (t, J
= 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 1H), 6.90-6.88 (m, 1H), 2.47-2.43 (m, 2H), 2.36-2.32 (m, 2H), 1.79-1.69
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(m, 4H). C{1H} NMR (150 MHz, CDCl3): δ 190.8, 143.3, 142.4, 141.5, 139.1, 139.0, 130.1, 127.1, 125.9,
125.0, 123.0, 26.3, 24.6, 22.2, 21.9. IR (cm-1): 2925 (m), 2855 (m), 1625 (s), 1513 (m). HRMS: Calculated
for C15H14NaOS ([M+Na]+): 265.0658. Found: 265.0669.
Cyclohex-1-en-1-yl(5-methylfuran-2-yl)methanone, (5e). Prepared from 1-cyclohexene-1-
carboxaldehyde (2) and 2-methylfuran. Purified via silica gel column chromatography using 10% EtOAc
in hexanes, affording a light yellow oil (219 mg, 1.15 mmol, 79% yield). TLC: Rƒ = 0.31, (10% EtOAc in
hexanes). 1H NMR (600 MHz, CDCl3): δ 6.97 (d, J = 3.4 Hz, 1H), 6.84-6.81 (m, 1H), 6.12 (d, J = 3.1 Hz, 1H),
2.40 (s, 3H), 2.39-2.36 (m, 2H), 2.29-2.24 (m, 2H), 1.73-1.64 (m, 4H). C{1H} NMR (150 MHz, CDCl3): δ
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184.0, 157.9, 151.0, 139.4, 138.6, 121.1, 108.6, 26.1, 24.4, 22.2, 21.9, 14.3. IR (cm-1): 2925 (m), 2857
(m), 1632 (s), 1512 (s). HRMS: Calculated for C12H14NaO2 ([M+Na]+): 213.0886. Found: 213.0890.
Cyclohex-1-en-1-yl(4,5-dimethylfuran-2-yl)methanone, (5f). Prepared from 1-cyclohexene-1-
carboxaldehyde (2) and 2,3-dimethylfuran. Purified via silica gel column chromatography using 10%
EtOAc in hexanes, affording a light yellow oil (127 mg, 0.62 mmol, 39% yield). TLC: Rƒ = 0.31, (10% EtOAc
1
in hexanes). H NMR (600 MHz, CDCl3): δ 6.86 (s, 1H), 6.80-6.77 (m, 1H), 2.39-2.34 (m, 2H), 2.29 (s, 3H),
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2.27-2.23 (m, 2H), 1.97 (s, 3H), 1.71-1.63 (m, 4H). C{1H} NMR (150 MHz, CDCl3): δ 184.0, 153.9, 149.6,
138.9, 138.6, 123.3, 117.2, 26.1, 24.5, 22.2, 21.9, 12.2, 9.9. IR (cm-1): 2927 (m), 2859 (m), 1633 (s), 1515
(s). HRMS: Calculated for C13H16NaO2 ([M+Na]+): 227.1043. Found: 227.1048.
Cyclohex-1-en-1-yl(furan-3-yl)methanone,
carboxaldehyde (2) and 3-bromofuran. Purified via silica gel column chromatography using 20% EtOAc
(5g).
Prepared
from
1-cyclohexene-1-
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in hexanes, affording a yellow oil (240 mg, 1.36 mmol, 68% yield). TLC: Rƒ = 0.58, (20% EtOAc in
hexanes). 1H NMR (600 MHz, CDCl3): δ 7.80 (s, 1H), 7.42 (t, J = 1.7 Hz, 1H), 6.80-6.77 (m, 1H), 6.75 (d, J =
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1.8 Hz, 1H), 2.41-2.37 (m, 2H), 2.29-2.25 (m, 2H), 1.74-1.65 (m, 4H). C{1H} NMR (150 MHz, CDCl3): δ
190.7, 146.8, 143.7, 140.5, 140.3, 126.4, 110.5, 26.2, 24.2, 22.2, 22.0. IR (cm-1): 2927 (s), 2857 (m), 1639
(s). HRMS: Calculated for C11H12NaO2 ([M+Na]+): 199.0730. Found: 199.0735.
Cyclohept-1-en-1-yl(furan-2-yl)methanone,
(6a).
Prepared
from
1-cycloheptene-1-
carboxaldehyde (3)48 and furan. Purified via silica gel column chromatography using 10% EtOAc in
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hexanes, affording a brown amorphous solid (273 mg, 1.43 mmol, 72% yield). TLC: Rf = 0.36, (10% EtOAc
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in hexanes). H NMR (600 MHz, CDCl3): δ 7.60 (s, 1H), 7.03 (d, J = 3.5 Hz, 1H), 6.98 (t, J = 6.7 Hz, 1H),
6.50-6.48 (m, 1H), 2.58-2.55 (m, 2H), 2.40-2.35 (m, 2H), 1.84-1.79 (m, 2H), 1.62-1.55 (m, 4H). 13C{1H}
NMR (150 MHz, CDCl3): δ 185.1, 152.3, 146.6, 145.2, 145.1, 119.2, 111.8, 32.5, 29.5, 28.4, 26.8, 26.2. IR
(cm-1): 2922 (s), 2851 (m), 1640 (s), 1631 (s), 1466 (s). HRMS: Calculated for C24H28NaO4 ([2M+Na]+):
403.1880. Found: 403.1885.
Cyclohept-1-en-1-yl(thiophen-2-yl)methanone, (6b). Prepared from 1-cycloheptene-1-
carboxaldehyde (3)48 and thiophene. Purified via silica gel column chromatography using 10% EtOAc in
hexanes, affording a brown solid (mp = 40-41 °C) (488 mg, 2.37 mmol, 79% yield). TLC: Rf = 0.50, (10%
EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.60 (d, J = 5.0 Hz, 1H), 7.56 (d, J = 3.7 Hz, 1H), 7.09 (t, J =
4.4 Hz, 1H), 6.87 (t, J = 6.6 Hz, 1H), 2.60-2.56 (m, 2H), 2.40-2.36 (m, 2H), 1.86-1.81 (m, 2H), 1.63-1.58 (m,
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4H). C{1H} NMR (150 MHz, CDCl3): δ 190.5, 145.5, 144.8, 144.0, 133.4, 133.1, 127.7, 32.5, 29.4, 29.0,
26.8, 26.3. IR (cm-1): 2920 (s), 2850 (m), 1625 (s), 1413 (s). HRMS: Calculated for C24H28NaO2S2
([2M+Na]+): 435.1423. Found: 435.1434.
Benzofuran-2-yl(cyclohept-1-en-1-yl)methanone, (6c). Prepared from 1-cycloheptene-1-
carboxaldehyde (3)48 and 2,3-benzofuran. Purified via silica gel column chromatography using 10%
EtOAc in hexanes, affording a yellow-brown solid (mp = 62-64 °C) (554 mg, 2.31 mmol, 77% yield). TLC:
Rf = 0.49, (10% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.69 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 8.4 Hz,
1H), 7.45 (t, J = 7.8 Hz, 1H), 7.35 (s, 1H), 7.30 (t, J = 7.5 Hz, 1H), 7.14 (t, J = 6.6 Hz, 1H), 2.66-2.62 (m, 2H),
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2.46-2.41 (m, 2H), 1.89-1.83 (m, 2H), 1.67-1.60 (m, 4H). C{1H} NMR (150 MHz, CDCl3): δ 186.7, 156.0,
152.5, 146.5, 145.4, 127.9, 127.2, 123.9, 123.2, 115.0, 112.7, 32.5, 29.7, 28.4, 26.8, 26.2. IR (cm-1): 2921
(m), 2851 (w), 1637 (s), 1547 (s). HRMS: Calculated for C32H32NaO4 ([2M+Na]+): 503.2193. Found:
503.2207.
(5,6-Dihydro-2H-pyran-3-yl)(furan-2-yl)methanone, (7a). Prepared from 5,6-dihydro-2H-pyran-
3-carbaldehyde (4)49 and furan. Purified via silica gel column chromatography using 33% EtOAc in
hexanes, affording a yellow-brown solid (mp = 39-41 °C) (178 mg, 1.00 mmol, 60% yield). TLC: Rƒ = 0.10,
(10% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.62 (d, J = 0.9 Hz, 1H), 7.21-7.18 (m, 1H), 7.16 (d, J
= 3.5 Hz, 1H), 6.53 (dd, J = 3.5 Hz, 1.7 Hz, 1H), 4.49-4.47 (m, 2H), 3.83 (t, J = 5.5 Hz, 2H), 2.45-2.40 (m,
2H). 13C{1H} NMR (150 MHz, CDCl3): δ 181.0, 152.2, 146.7, 138.3, 137.5, 119.1, 112.1, 65.0, 63.7, 25.9. IR
(cm-1): 2924 (s), 2857 (m), 1630 (s), 1463 (m). HRMS: Calculated for C10H10NaO3 ([M+Na]+): 201.0522.
Found: 201.0526.
(5,6-Dihydro-2H-pyran-3-yl)(thiophen-2-yl)methanone, (7b). Prepared from 5,6-dihydro-2H-
pyran-3-carbaldehyde (4)49 and thiophene. Purified via silica gel column chromatography using 20%
EtOAc in hexanes, affording a yellow solid (mp = 63-64 °C) (266 mg, 1.37 mmol, 68% yield). TLC: Rƒ =
0.35, (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.65-7.63 (m, 2H), 7.12 (dd, J = 4.6 Hz, 3.9 Hz,
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1H), 6.95-6.92 (m, 1H), 4.50-4.48 (m, 2H), 3.85 (t, J = 5.5 Hz, 2H), 2.44-2.40 (m, 2H). C{1H} NMR (150
MHz, CDCl3): δ 186.8, 142.8, 138.2, 137.4, 133.5, 133.3, 127.9, 65.3, 63.7, 25.8. IR (cm-1): 2962 (w), 2922
(w), 2850 (w), 1617 (s), 1415 (s). HRMS: Calculated for C10H10NaO2S ([M+Na]+): 217.0294. Found:
217.0298.
Benzofuran-2-yl(5,6-dihydro-2H-pyran-3-yl)methanone, (7c). Prepared from 5,6-dihydro-2H-
pyran-3-carbaldehyde (4)49 and 2,3-benzofuran. Purified via silica gel column chromatography using
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33% EtOAc in hexanes, affording a yellow solid (mp = 80-81 °C) (355 mg, 1.55 mmol, 78% yield). TLC: Rƒ
= 0.36, (20% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.69 (d, J = 7.8 Hz, 1H), 7.57 (d, J = 8.4 Hz,
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1H), 7.47-7.44 (m, 2H), 7.36-7.33 (m, 1H), 7.30 (t, J = 7.5 Hz, 1H), 4.54-4.51 (m, 2H), 3.85 (t, J = 5.5 Hz,
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2H), 2.49-2.45 (m, 2H). C{1H} NMR (150 MHz, CDCl3): δ 182.6, 155.9, 152.1, 139.5, 137.7, 128.2, 126.9,
124.1, 123.3, 114.9, 112.5, 64.9, 63.6, 26.0. IR (cm-1): 2919 (w), 2850 (w), 1634 (m), 1548 (m). HRMS:
Calculated for C14H12NaO3 ([M+Na]+): 251.0679. Found: 251.0689.
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Benzo[b]thiophen-2-yl(5,6-dihydro-2H-pyran-3-yl)methanone, (7d). Prepared from 5,6-
dihydro-2H-pyran-3-carbaldehyde (4)49 and benzo[b]thiophene.
Purified via silica gel column
chromatography using 33% acetone in hexanes, affording a yellow solid (mp = 71-75 °C) (406 mg, 1.66
1
mmol, 83% yield). TLC: Rƒ = 0.34, (20% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.88 (dd, J = 8.0
Hz, 4.4 Hz, 2H), 7.86 (s, 1H), 7.47 (t, J = 7.6 Hz, 1H), 7.42 (t, J = 7.5 Hz, 1H), 7.04-7.02 (m, 1H), 4.54-4.52
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(m, 2H), 3.88 (t, J = 5.5 Hz, 2H), 2.49-2.45 (m, 2H). C{1H} NMR (150 MHz, CDCl3): δ 188.1, 142.4, 142.3,
139.0, 138.20, 138.16, 130.4, 127.4, 126.0, 125.2, 123.0, 65.2, 63.7, 25.9. IR (cm-1): 2964 (w), 2924 (w),
2850 (w), 1619 (s). HRMS: Calculated for C14H12NaO2S ([M+Na]+): 267.0450. Found: 267.0452.
(5,6-Dihydro-2H-pyran-3-yl)(furan-3-yl)methanone, (7g). Prepared from 5,6-dihydro-2H-pyran-
3-carbaldehyde (4)49 and 3-bromofuran. Purified via silica gel column chromatography using 20% EtOAc
in hexanes, affording a yellow solid (mp = 52-57 °C) (192 mg, 1.08 mmol, 54% yield). TLC: Rƒ = 0.27, (20%
EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.86 (s, 1H), 7.45 (s, 1H), 6.92-6.90 (m, 1H), 6.75 (s, 1H),
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4.47 (s, 2H), 3.82 (t, J = 5.5 Hz, 2H), 2.42-2.38 (m, 2H). C{1H} NMR (150 MHz, CDCl3): δ 188.1, 146.9,
144.0, 139.6, 137.0, 125.9, 110.2, 65.1, 63.7, 25.9. IR (cm-1): 2958 (m), 2924 (s), 2853 (m), 1639 (m).
HRMS: Calculated for C10H10NaO3 ([M+Na]+): 201.0522. Found: 201.0521.
Flow photo-Nazarov reaction—general procedure. In a round-bottom flask, aryl vinyl ketone
was dissolved in glacial acetic acid to the desired concentration (0.056 M, 0.028 M, or 0.014 M) and
degassed with argon for 15 minutes. The solution was then taken up in a syringe, which was placed on a
syringe pump and connected to FEP (fluorinated ethylene propylene) tubing (1.6 mm ID, 3.2 mm OD, 3.0
m length) wrapped around a photochemical double-walled borosilicate glass immersion well housing a
medium pressure mercury vapor immersion lamp (450 W, 125-145 V, 3.6 A, 244.4 mm total length,
131.5 mm arc).37 Ice-cooled water was flowed through the immersion well for the duration of the
reaction. The solution was pumped through the tubing at specified flow rates to achieve residence times
ranging from 2.3 min to 34 mins (See Tables SI-1 and SI-2 in the Supporting Information), and collected
in a round-bottom flask. When all of the reaction solution had been pumped into the tubing, glacial
acetic acid was pumped through the tubing at the same flow rate until all solution containing the
reaction mixture was collected. The reaction mixture was diluted with ether (20 mL) and then washed
with a solution of saturated aqueous sodium bicarbonate (2 × 25 mL). The combined aqueous layers
were extracted with diethyl ether (2 × 25 mL), and the combined organic layers were washed with brine
(25 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The crude
reaction mixtures were purified via silica gel column chromatography (see details below for each
product). When hexafluoroisopropanol was used as solvent instead of acetic acid, the reaction mixture
was directly concentrated after passing through the flow photo-reactor, and then purified via silica gel
column chromatography.
(3bR,7aS)-3b,4,5,6,7,7a-Hexahydro-8H-indeno[2,1-b]furan-8-one, (8). Synthesized from 5a
(0.056 M in AcOH, 6.8 min exposure time) and purified via silica gel column chromatography using 10%
EtOAc in hexanes to afford a clear, colorless oil (44.9 mg, 0.25 mmol, 86% yield). TLC: Rƒ = 0.25, (10%
EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.74 (d, J = 0.8 Hz, 1H), 6.48 (d, J = 0.9 Hz, 1H), 3.19 (ddd,
J = 8.5 Hz, 6.0 Hz, 6.0 Hz, 1H), 2.99 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 2.07-2.01 (m, 1H), 1.98-1.92 (m,
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1H), 1.83-1.78 (m, 1H), 1.55-1.48 (m, 2H), 1.44-1.30 (m, 3H). C{1H} NMR (150 MHz, CDCl3): δ 191.0,
159.8, 154.6, 153.4, 109.3, 52.3, 32.7, 28.2, 23.3, 20.9, 20.7. IR (cm-1): 2932 (m), 2857 (m), 1700 (s).
HRMS: Calculated for C11H12NaO2 ([M+Na]+): 199.0730. Found: 199.0739.
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(3bR,7aS)-2-Methyl-3b,4,5,6,7,7a-hexahydro-8H-indeno[2,1-b]furan-8-one, (9). Synthesized
from 5e (0.014 M in AcOH, 3.4 min exposure time) and purified via silica gel column chromatography
using 10% EtOAc in hexanes to afford a clear, colorless oil (28.3 mg, 0.15 mmol, 57% yield). TLC: Rƒ =
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0.19, (10% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 6.12 (s, 1H), 3.13 (ddd, J = 8.2 Hz, 6.0 Hz, 6.0
Hz, 1H), 2.92 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 2.40 (s, 3H), 2.02-1.96 (m, 1H), 1.94-1.87 (m, 1H), 1.83-
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1.75 (m, 1H), 1.53-1.46 (m, 2H) 1.44-1.28 (m, 3H). C{1H} NMR (150 MHz, CDCl3): δ 190.1, 165.3, 161.8,
153.0, 106.1, 51.6, 32.9, 27.9, 23.2, 20.7, 20.5, 15.0. IR (cm-1): 2927 (m), 2856 (m), 1700 (s). HRMS:
Calculated for C12H14NaO2 ([M+Na]+): 213.0886. Found: 213.0900.
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(3bR,7aS)-2,3-Dimethyl-3b,4,5,6,7,7a-hexahydro-8H-indeno[2,1-b]furan-8-one,
(10).
Synthesized from 5f (0.014 M in AcOH, 3.4 min exposure time) and purified via silica gel column
chromatography using 10% EtOAc in hexanes to afford a yellow oil (33.8 mg, 0.17 mmol, 68% yield). TLC:
Rƒ = 0.20, (10% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 3.13 (ddd, J = 8.7 Hz, 6.0 Hz, 6.0 Hz, 1H),
2.92 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 2.31 (s, 3H), 2.06-2.00 (m, 1H), 1.98 (s, 3H), 1.96-1.89 (m, 1H),
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1.83-1.76 (m, 1H), 1.55-1.48 (m, 2H) 1.46-1.30 (m, 3H). C{1H} NMR (150 MHz, CDCl3): δ 190.0, 161.9,
161.2, 151.5, 115.1, 51.6, 32.6, 27.1, 23.2, 20.8, 20.5, 12.8, 8.7. IR (cm-1): 2927 (m), 2855 (m), 1700 (s),
1545 (m), 1457 (m). HRMS: Calculated for C13H16NaO2 ([M+Na]+): 227.1043. Found: 227.1044.
(6aS,10aR)-6a,7,8,9,10,10a-Hexahydro-6H-indeno[2,1-b]benzofuran-6-one, (11). Synthesized
from 5c (0.056 M in AcOH, 6.8 min exposure time) and purified via silica gel column chromatography
using 10% EtOAc in hexanes to afford a yellow solid (mp = 97-108 °C) (25.3 mg, 0.11 mmol, 51% yield).
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TLC: Rf = 0.32, (10% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 7.8 Hz, 1H), 7.60 (d, J =
8.5 Hz, 1H), 7.50 (t, J = 8.4 Hz, 7.3 Hz, 1H), 7.35 (t, J = 7.5 Hz, 1H), 3.51 (ddd, J = 6.4 Hz, 6.4 Hz, 6.4 Hz,
1H), 3.10 (ddd, J = 6.1 Hz, 6.1 Hz, 6.1 Hz, 1H), 2.28-2.20 (m, 1H), 2.07-2.00 (m, 1H), 1.93-1.86 (m, 1H),
1.63-1.38 (m, 5H). 13C{1H} NMR (150 MHz, CDCl3): δ 193.4, 162.0, 155.5, 154.9, 129.1, 124.6, 124.0,
122.3, 114.0, 51.8, 32.8, 27.9, 23.3, 20.8, 20.7. IR (cm-1): 2927 (m), 1706 (s). HRMS: Calculated for
C15H14NaO2 ([M+Na]+): 249.0886. Found: 249.0892.
(4aS,8aR)-4a,5,6,7,8,8a-Hexahydro-4H-indeno[1,2-b]furan-4-one, (12). Synthesized from 5g
(0.056 M in AcOH, 3.4 min exposure time) and purified via silica gel column chromatography using 10%
EtOAc in hexanes to afford an orange-yellow solid (mp = 59-60 °C) (42.4 mg, 0.24 mmol, 91% yield). TLC:
Rƒ = 0.44, (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.50 (d, J = 1.9 Hz, 1H), 6.51 (d, J = 1.9 Hz,
1H), 3.33 (ddd, J = 6.5 Hz, 6.5 Hz, 6.5 Hz, 1H), 3.10 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 2.07-1.96 (m, 2H),
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1.83-1.76 (m, 1H), 1.56-1.35 (m, 5H). C{1H} NMR (150 MHz, CDCl3): δ 198.4, 185.5, 149.2, 126.6, 105.4,
53.5, 35.0, 25.9, 22.7, 20.4, 20.3. IR (cm-1): 2935 (m), 2865 (m), 1705 (s). HRMS: Calculated for
C11H12NaO2 ([M+Na]+): 199.0730. Found: 199.0734.
(3bR,7aS)-3b,4,5,6,7,7a-Hexahydro-8H-indeno[2,1-b]thiophen-8-one, (13). Synthesized from 5b
(0.014 M in AcOH, 3.4 min exposure time) and purified via silica gel column chromatography using 10%
EtOAc in hexanes to afford a clear, colorless oil (36.6 mg, 0.19 mmol, 70% yield). TLC: Rƒ = 0.30, (10%
EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.87 (d, J = 4.7 Hz, 1H), 7.04 (d, J = 4.7 Hz, 1H), 3.34 (ddd,
J = 8.5 Hz, 6.4 Hz, 6.4 Hz, 1H), 3.05 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 2.10-2.00 (m, 2H), 1.82-1.77 (m,
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1H), 1.57-1.46 (m, 2H), 1.44-1.29 (m, 3H). C{1H} NMR (150 MHz, CDCl3): δ 199.5, 172.5, 140.1, 139.7,
123.1, 52.8, 37.1, 29.5, 23.6, 21.6, 21.5. IR (cm-1): 2928 (m), 2853 (m), 1696 (s), 1426 (m). HRMS:
Calculated for C11H12NaOS ([M+Na]+): 215.0501. Found: 215.0512.
(6aS,10aR)-6a,7,8,9,10,10a-Hexahydro-6H-benzo[b]indeno[1,2-d]thiophen-6-one,
(14).
Synthesized from 5d (0.014 M in AcOH, 3.4 min exposure time) and purified via silica gel column
chromatography using 10% EtOAc in hexanes to afford a yellow solid (mp = 143-147 °C) (21.2 mg, 0.087
mmol, 62% yield). TLC: Rƒ = 0.57, (20% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.91 (d, J = 8.8 Hz,
2H), 7.50-7.43 (m, 2H), 3.65 (ddd, J = 9.3 Hz, 6.2 Hz, 6.2 Hz, 1H), 3.13 (ddd, J = 6.5 Hz, 6.5 Hz, 6.5 Hz, 1H),
2.36-2.30 (m, 1H), 2.19 (dddd, J = 14.7 Hz, 5.1 Hz, 5.1 Hz, 5.1 Hz, 1H), 1.87-1.81 (m, 1H), 1.66-1.54 (m,
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2H), 1.50-1.33 (m, 3H). C{1H} NMR (150 MHz, CDCl3): δ 200.3, 168.0, 148.6, 139.7, 134.1, 127.9, 125.1,
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124.7, 124.0, 52.0, 36.9, 29.1, 23.1, 21.5, 21.3. IR (cm-1): 2924 (m), 2852 (m), 1694 (s). HRMS: Calculated
for C15H14NaOS ([M+Na]+): 265.0658. Found: 265.0659.
(3bR,8aS)-4,5,6,7,8,8a-Hexahydroazuleno[2,1-b]furan-9(3bH)-one, (15). Synthesized from 6a
(0.028 M in HFIP, 3.4 min exposure time) and purified via silica gel column chromatography using 10%
EtOAc in hexanes to afford a yellow oil (60.6 mg, 0.32 mmol, 94% yield). TLC: Rf = 0.34, (20% EtOAc in
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hexanes). H NMR (600 MHz, CDCl3): δ 7.74 (s, 1H), 6.46 (s, 1H), 3.32-3.27 (m, 1H), 3.08-3.03 (m, 1H),
2.12-2.06 (m, 1H), 2.05-1.99 (m, 1H), 1.80-1.53 (m, 5H), 1.44-1.30 (m, 3H). 13C{1H} NMR (150 MHz,
CDCl3): δ 190.9, 160.0, 154.5, 153.9, 109.3, 58.3, 38.5, 31.3, 31.2, 28.4, 28.30, 28.25. IR (cm-1): 2923 (m),
2851 (w), 1699 (m), 1429 (m). HRMS: Calculated for C12H15O2 ([M+H]+): 191.1067. Found: 191.1081.
(6aS,11aR)-7,8,9,10,11,11a-Hexahydroazuleno[2,1-b]benzofuran-6(6aH)-one, (16). Synthesized
from 6c (0.056 M in HFIP, 6.8 min exposure time) and purified via silica gel column chromatography
using 20% hexanes in CH2Cl2 to afford a white solid (mp = 116-117 °C) (23.6 mg, 0.0982 mmol, 57%
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yield). TLC: Rf = 0.36, (10% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 7.8 Hz, 1H), 7.58
(d, J = 8.4 Hz, 1H), 7.49 (t, J = 7.8 Hz, 1H), 7.33 (t, J = 7.5 Hz, 1H), 3.63-3.59 (m, 1H), 3.18-3.14 (m, 1H),
2.33-2.27 (m, 1H), 2.20-2.13 (m, 1H), 1.85-1.65 (m, 5H), 1.54-1.34 (m, 3H). 13C{1H} NMR (150 MHz,
CDCl3): δ 199.3, 162.2, 155.4, 154.7, 129.2, 124.5, 124.0, 122.5, 113.9, 57.8, 38.9, 31.2, 30.9, 28.5, 28.4.
IR (cm-1): 2923 (s), 2851 (m), 1701 (s). HRMS: Calculated for C32H32NaO4 ([2M+Na]+): 503.2193. Found:
503.2211.
(3bR,8aS)-4,5,6,7,8,8a-Hexahydroazuleno[2,1-b]thiophen-9(3bH)-one, (17). Synthesized from
6b (0.014 M in HFIP, 3.4 min exposure time) and purified via silica gel column chromatography using
10% EtOAc in hexanes to afford a light brown solid (cis: trans dr = 20:1) (48.7 mg, 0.24 mmol, 97% yield).
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TLC: Rf = 0.31, (10% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.88 (d, J = 4.8 Hz, 1H), 7.03 (d, J =
4.6 Hz, 1H), 3.51-3.46 (m, 1H), 3.17-3.12 (m, 1H), 2.16-2.07 (m, 2H), 1.83-1.61 (m, 5H), 1.49-1.32 (m, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 199.8, 172.6, 140.6, 140.3, 123.3, 58.3, 43.1, 32.0, 31.4, 28.6, 28.5,
28.3. IR (cm-1): 2923 (m), 2850 (w), 1692 (s), 1424 (m). HRMS: Calculated for C24H28NaO2S2 ([2M+Na]+):
435.1423. Found: 435.1441.
Synthesis of vinyl stannane 18. Prepared according to a modified literature procedure.42 To a
solution of diisopropylamine (2.11 mL, 15.0 mmol, 3.00 equiv) in anhydrous THF (75 mL) at 0 °C was
added n-BuLi (1.6 M in hexanes, 9.36 mL, 15.0 mmol, 3.00 equiv). After 15 min, tributyltin hydride (3.95
mL, 15.0 mmol, 3.00 equiv) was added at 0 °C. After 15 min, the reaction was cooled to -78 °C in a dry
ice/acetone bath. Tetrahydro-4H-pyran-4-one (0.46 mL, 4.99 mmol, 1.00 equiv) was added, and the
reaction was stirred for 1 h. Methanesulfonyl chloride (1.55 mL, 20.0 mmol, 4.00 equiv) and
triethylamine (5.21 mL, 37.4 mmol, 7.50 equiv) were added, and the reaction mixture was warmed to
room temperature and stirred. After 21 h, the mixture was transferred to a separatory funnel with
hexane (150 mL), and washed with water (3 × 100 mL) (Brine used to separate emulsions). The
combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure.
The crude reaction mixture was purified via silica gel column chromatography, using hexanes to first
elute the nonpolar alkyl tin compounds, and then using 20% EtOAc in hexanes to elute 18 as a light
yellow solid (934 mg, 2.50 mmol, 50% yield). Spectroscopic data were consistent with literature
values.42
Synthesis of vinyl stannanes 19-20. Prepared according to a modified literature procedure.42 To
a solution of diisopropylamine (4.00 equiv) in anhydrous THF (0.2 mmol diisopropylamine/mL) at 0 °C
was added n-BuLi (1.6 M in hexanes, 4.00 equiv). After 20 min, tributyltin hydride (4.00 equiv) was
added at 0 °C. After an additional 20 min, the reaction was cooled to -78 °C in a dry ice/acetone bath, N-
Boc piperidin-4-one or N-tosylpiperidin-4-one (1.00 equiv) was added, and the reaction was stirred for
1.5 h. Methanesulfonyl chloride (4.00 equiv) and triethylamine (7.50 equiv) were added, and the
reaction was warmed to room temperature and stirred. After 4 h, additional methanesulfonyl chloride
(4.00 equiv) and triethylamine (7.50 equiv) were added. After stirring a further 4 h, methanesulfonyl
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chloride (4.00 equiv) and triethylamine (7.50 equiv) were added a third time. After 16-20 h, the reaction
mixture was transferred to a separatory funnel with hexane (100 mL), and washed with water (3 × 100
mL) (Brine used to separate emulsions). The combined aqueous layers were extracted with hexane (100
mL), and the combined organic layers were dried over magnesium sulfate and concentrated under
reduced pressure. The crude reaction mixture was purified via silica gel column chromatography, using
hexanes to first elute the nonpolar alkyl tin compounds, and then 10% EtOAc in hexanes to elute the
desired vinyl stannane. Vinyl stannane 19 was isolated as a yellow oil (1.60 g, 3.39 mmol, 68% yield)
whose spectroscopic data were consistent with literature values.42 Vinyl stannane 20 was isolated as a
yellow oil (1.02 g, 1.94 mmol, 49% yield).
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1-Tosyl-4-(tributylstannyl)-1,2,3,6-tetrahydropyridine, (20). TLC: Rf = 0.68, (20% EtOAc in
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hexanes). H NMR (300 MHz, CDCl3): δ 7.66 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.0 Hz, 2H), 5.77-5.56 (m, 1H),
3.60-3.57 (m, 2H), 3.13 (t, J = 5.6 Hz, 2H), 2.42 (s, 3H), 2.36-2.31 (m, 2H), 1.49-1.21 (m, 12H), 0.97-0.81
(m, 15H). 13C{1H} NMR (75 MHz, CDCl3): δ 143.6, 139.2, 133.5, 131.4, 129.8, 127.9, 46.5, 43.3, 31.7, 29.3,
27.5, 21.7, 13.9, 9.2.
IR (cm-1): 2922 (m), 1352 (w), 1166 (m).
HRMS: Calculated for
C24H42NO2SSn([M+H]+): 528.1953. Found: 528.1952.
Synthesis of ketones 21-25 (Stille coupling—procedure A). Prepared according to a modified
literature procedure.41 To a solution of vinylstannane (18-20, 1.00 equiv) and acyl chloride (1.10-1.50
equiv) in toluene (0.28 mmol vinylstannane/mL) was added Pd(PPh3)2Cl2 (0.05 equiv). The reaction
mixture was then refluxed or heated in a microwave reactor in a sealed vial (see details for individual
substrates, below). Upon completion, the reaction mixture was cooled to room temperature, filtered
through a short pad of silica gel, and concentrated under reduced pressure. The crude reaction mixture
was purified via silica gel column chromatography, affording ketones 21-25 (see details below for each
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product). If alkyl tin byproducts were observed by H NMR, the product was further passed through a
short column of 10% KF in silica gel to remove them.
(3,6-Dihydro-2H-pyran-4-yl)(furan-2-yl)methanone, (21). Prepared using a modification of Stille
coupling procedure A (1.00 equiv 2-furoyl chloride, 1.10 equiv vinyl stannane 18, 0.025 equiv
Pd(PPh3)2Cl2), refluxing in toluene for 18 h. The crude reaction mixture was purified via silica gel column
chromatography using 20% EtOAc in hexanes, ramping to 33% EtOAc in hexanes, affording 21 as a
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yellow oil (352 mg, 1.97 mmol, 86% yield). TLC: Rf = 0.33, (33% EtOAc in hexanes). H NMR (600 MHz,
CDCl3): δ 7.62 (s, 1H), 7.16 (d, J = 3.3 Hz, 1H), 7.00 (s, 1H), 6.54-6.52 (m, 1H), 4.37 (s, 2H), 3.86 (t, J = 5.4
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Hz, 2H), 2.53 (s, 2H). C{1H} NMR (150 MHz, CDCl3): δ 181.6, 152.3, 146.7, 138.6, 135.4, 119.2, 112.1,
65.3, 64.4, 24.3. IR (cm-1): 2923 (w), 2851 (w), 1633 (s), 1466 (s). HRMS: Calculated for C10H10NaO3
([M+Na]+): 201.0522. Found: 201.0549.
(3,6-Dihydro-2H-pyran-4-yl)(thiophen-2-yl)methanone, (22). Prepared using vinyl stannane 18
and Stille coupling procedure A (1.10 equiv 2-thiophenecarbonyl chloride), in a sealed vial in a
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microwave reactor set to ramp to 170 °C over 5 min, and then hold at 170 C for 30 min. The crude
reaction mixture was purified via silica gel column chromatography using 20% EtOAc in hexanes,
ramping to 33% EtOAc in hexanes, affording 22 as a colorless oil (314 mg, 1.62 mmol, 77% yield). TLC: Rf
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= 0.55, (20% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.66-7.63 (m, 2H), 7.12 (t, J = 4.3 Hz, 1H),
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6.75 (s, 1H), 4.36 (s, 2H), 3.87 (t, J = 5.4 Hz, 2H), 2.55 (s, 2H). C{1H} NMR (150 MHz, CDCl3): δ 187.3,
142.9, 137.7, 136.1, 133.6, 133.3, 127.9, 65.2, 64.4, 24.6. IR (cm-1): 2922 (w), 2852 (w), 1621 (s), 1414 (s).
HRMS: Calculated for C10H10NaO2S ([M+Na]+): 217.0294. Found: 217.0316.
Benzofuran-2-yl(3,6-dihydro-2H-pyran-4-yl)methanone, (23). Prepared using vinyl stannane 18
and Stille coupling procedure A (1.10 equiv 1-benzofuran-2-carbonyl chloride), in a sealed vial in a
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microwave reactor set to ramp to 170 C over 5 min, and then hold at 170 °C for 30 min. The crude
reaction mixture was purified via silica gel column chromatography using 20% EtOAc in hexanes,
ramping to 33% EtOAc in hexanes, affording 23 as a white solid (mp = 93-94 °C) (231 mg, 1.01 mmol,
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55% yield). TLC: Rf = 0.56, (20% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 7.9 Hz, 1H),
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7.59 (d, J = 8.4 Hz, 1H), 7.49-7.44 (m, 2H), 7.31 (t, J = 7.5 Hz, 1H), 7.16 (s, 1H), 4.43 (s, 2H), 3.90 (t, J = 5.4
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Hz, 2H), 2.58 (s, 2H). C{1H} NMR (150 MHz, CDCl3): δ 183.3, 155.9, 152.3, 139.8, 135.7, 128.2, 127.0,
124.1, 123.3, 115.0, 112.6, 65.3, 64.4, 24.3. IR (cm-1): 2924 (w), 2855 (w), 1638 (m), 1549 (m). HRMS:
Calculated for C14H12NaO3 ([M+Na]+): 251.0679. Found: 251.0708.
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tert-Butyl 4-(furan-2-carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate, (24). Prepared using
vinyl stannane 19 and Stille coupling procedure A (1.50 equiv 2-furoyl chloride), in a sealed vial in a
microwave reactor set to ramp to 125 °C over 5 min, and then hold at 125 °C for 15 min. The crude
reaction mixture was purified via silica gel column chromatography using 20% EtOAc in hexanes,
ramping to 33% EtOAc in hexanes, affording 24 as a yellow oil (95.1 mg, 0.34 mmol, 70% yield). TLC: Rf
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=0.28, (50% EtOAc in hexanes). H NMR (300 MHz, CDCl3): δ 7.62-7.60 (m, 1H), 7.15 (d, J = 3.6 Hz, 1H),
6.92 (s, 1H), 6.53 (dd, J = 3.5 Hz, 1.7 Hz, 1H), 4.18-4.14 (m, 2H), 3.55 (t, J = 5.7 Hz, 2H), 2.52, (s, 2H), 1.48
13
(s, 9H). C{1H} NMR (75 MHz, CDCl3): δ 181.8, 154.7, 152.1, 146.7, 137.0-135.7 (broad), 136.4, 119.3,
112.1, 80.2, 44.3-43.0 (broad), 40.8-39.5 (broad), 28.6, 24.5. IR (cm-1): 2957 (w), 2922 (w), 1696 (s), 1466
(s). HRMS: Calculated for C15H19NNaO4 ([M+Na]+): 300.1206. Found: 300.1216.
Furan-2-yl(1-tosyl-1,2,3,6-tetrahydropyridin-4-yl)methanone, (25).
Prepared using vinyl
stannane 20 and Stille coupling procedure A (1.50 equiv 2-furoyl chloride), heating in toluene at 90 °C
for 30 min. The crude reaction mixture was purified via silica gel column chromatography using 33%
EtOAc in hexanes, affording 25 as a white solid (mp = 165-168 °C) (134 mg, 0.40 mmol, 70% yield). TLC:
Rf = 0.55, (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.71 (d, J = 8.2 Hz, 2H), 7.62-7.60 (m, 1H),
7.34 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 3.6 Hz, 1H), 6.87-6.83 (m, 1H), 6.53 (dd, J = 3.5 Hz, 1.7 Hz, 1H), 3.86
(q, J = 2.9 Hz, 2H), 3.26 (t, J = 5.7 Hz, 2H), 2.66-2.59 (m, 2H), 2.44 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
181.4, 152.0, 147.0, 144.2, 136.2, 134.2, 133.2, 130.0, 127.9, 119.7, 112.3, 45.1, 42.8, 24.7, 21.8. IR (cm-
1): 2917 (w), 2849 (w), 1625 (m), 1163 (m). HRMS: Calculated for C17H17NNaO4S ([M+Na]+): 354.0771.
Found: 354.0773.
Synthesis of 26 and 27. To a solution of 1,2,5,6-tetrahydro-3-pyridinecarboxylic acid
hydrochloride (400 mg, 2.44 mmol, 1.00 equiv) in a mixture of DMF (7.2 mL) and water (4.8 mL) was
added triethylamine (0.85 mL, 6.1 mmol, 2.50 equiv). The reaction was stirred for 5 min at room
temperature, and then p-toluenesulfonyl chloride (698 mg, 3.66 mmol, 1.50 equiv) was added. The
reaction was stirred 22 h at room temperature, and then diluted with saturated aqueous NaHCO3 (15
mL) and EtOAc (10 mL). The layers were separated and the organic layer was extracted with saturated
aqueous NaHCO3 (3 × 10 mL). The combined aqueous layers were acidified with 36% hydrochloric acid
until a white precipitate formed. EtOAc (20 mL) was added to dissolve the precipitate and the layers
were separated. The aqueous layer was extracted with ethyl acetate (2 × 20 mL), and the combined
organic layers were washed with brine (4 × 15 mL), dried over sodium sulfate, and concentrated under
reduced pressure to afford 27 as a white solid (mp = 157-159 °C) (527 mg, 1.87 mmol, 77% yield).
Compound 26 was similarly prepared using Boc2O, affording a white solid (671 mg, 2.95 mmol,
97% yield) whose spectroscopic data were consistent with literature values.49a
1-Tosyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid, (27). TLC: Rf = 0.37, (50% acetone in
1
hexanes). H NMR (300 MHz, CDCl3): δ 7.69 (d, J = 8.3 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.14-7.09 (m, 1H),
3.80-3.77 (m, 2H), 3.18 (t, J = 5.7 Hz, 2H), 2.48-2.39 (m, 2H), 2.43 (s, 3H). 13C{1H} NMR (75 MHz, CDCl3): δ
170.2, 144.1, 140.2, 133.1, 130.0, 127.8, 126.6, 43.8, 41.8, 26.1, 21.7. IR (cm-1): 2845 (br), 1680 (s), 1648
(m). HRMS: Calculated for C13H16NO4S ([M+H]+): 282.0795. Found: 282.0800.
Synthesis of ketones 28 and 29 (Stille coupling—procedure B). Prepared according to a
modified literature procedure.41 To a solution of 27 (308 mg, 1.10 mmol, 1.00 equiv) in
dichloromethane (3.8 mL) was added oxalyl chloride (0.20 mL, 2.2 mmol, 2.00 equiv), followed by a drop
of dimethylformamide. The reaction was stirred for 1.25 h at room temperature and concentrated
under reduced pressure. The crude acid chloride intermediate was then dissolved in toluene (4 mL) and
transferred to a 20-mL microwave vial. 2-(Tributylstannyl)furan (0.38 mL, 1.21 mmol, 1.10 equiv) and
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Pd(PPh3)2Cl2 (38.6 mg, 0.060 mmol, 0.050 equiv) were then added to the vial. The sealed vial was placed
in a microwave reactor set to ramp to 170 °C over 5 min, and then hold at 170 °C for 30 min. Once the
microwave vial cooled to room temperature, the reaction mixture was filtered through a short pad of
silica gel (10% EtOAc in hexanes, then 66% EtOAc in hexanes), and concentrated under reduced
pressure. The crude reaction mixture was purified via silica gel column chromatography using 50%
EtOAc in hexanes. Alkyl tin byproducts were also observed by 1H NMR, so the product was run through
a short column of 10% KF in silica gel (50% EtOAc in hexanes), affording aryl vinyl ketone 29 as a light
yellow solid (mp = 118-119 °C) (295 mg, 0.89 mmol, 81% yield).
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Compound 28 was similarly prepared from 26; However, it was necessary to run the reaction on
small scale (0.29 mmol) in order to avoid significant decomposition (temperature in vial only reached
150 °C). Aryl vinyl ketone 28 was isolated as a yellow solid (mp = 69-75 °C) (66.8 mg, 0.24 mmol, 83%
yield).
tert-Butyl 5-(furan-2-carbonyl)-3,6-dihydropyridine-1(2H)-carboxylate, (28). TLC: Rf = 0.68,
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(50% EtOAc in hexanes). H NMR (300 MHz, CDCl3): δ 7.60-7.59 (m, 1H), 7.18-7.12 (m, 2H), 6.51 (dd, J =
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3.6 Hz, 1.7 Hz, 1H), 4.23 (s, 2H), 3.52 (t, J = 5.7 Hz, 2H), 2.44-2.36 (m, 2H), 1.45 (s, 9H). C{1H} NMR (75
MHz, CDCl3): δ 181.2, 155.0, 152.1, 146.7, 139.3 (br), 136.0 (br), 119.2, 112.1, 80.2, 42.8, 39.0 (br), 28.6,
25.9. IR (cm-1): 2977 (m), 2930 (m), 1700 (s), 1635 (s). HRMS: Calculated for C15H19NNaO4 ([M+Na]+):
300.1206. Found: 300.1236.
Furan-2-yl(1-tosyl-1,2,5,6-tetrahydropyridin-3-yl)methanone, (29). TLC: Rf = 0.56, (50% EtOAc
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in hexanes). H NMR (600 MHz, CDCl3): δ 7.70 (d, J = 7.3 Hz, 2H), 7.59 (s, 1H), 7.32 (d, J = 7.9 Hz, 2H),
7.12-7.08 (m, 2H), 6.53-6.50 (m, 1H), 3.91 (s, 2H), 3.23 (t, J = 5.8 Hz, 2H), 2.53-2.48 (m, 2H), 2.42 (s, 3H).
13C{1H} NMR (150 MHz, CDCl3): δ 180.5, 151.8, 146.9, 144.0, 138.5, 134.7, 133.3, 130.0, 127.9, 119.5,
112.2, 44.3, 42.1, 26.3, 21.7. IR (cm-1): 2920 (w), 2850 (w), 1632 (m), 1465 (m). HRMS: Calculated for
C17H17NNaO4S ([M+Na]+): 354.0771. Found: 354.0798.
(3aS,3bS,7aR,8aS)-8-Oxo-3a,3b,4,5,7a,8-hexahydrofuro[3',2':3,4]cyclopenta[1,2-c]pyran-
8a(7H)-yl acetate, (30). Synthesized from 7a (0.028 M in AcOH, 2.3 min exposure time) and purified via
silica gel column chromatography using 33% EtOAc in hexanes to afford a yellow solid (mp = 100-105 °C)
1
(27.1 mg, 0.11 mmol, 41% yield). TLC: Rƒ = 0.23, (33% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ
6.43 (dd, J = 2.7 Hz, 1.4 Hz, 1H), 5.25 (t, J = 2.9 Hz, 1H), 4.29 (dd, J = 12.1 Hz, 2.4 Hz, 1H), 3.82 (ddd, J =
11.5 Hz, 3.8 Hz, 3.8 Hz, 1H), 3.71 (ddd, J = 8.4 Hz, 2.9 Hz, 1.1 Hz, 1H), 3.60 (dd, J = 12.1 Hz, 4.7 Hz, 1H),
3.36 (ddd, J = 11.2 Hz, 11.2 Hz, 2.2 Hz, 1H), 3.16-3.12 (m, 1H), 2.80-2.73 (m, 1H), 2.08 (s, 3H), 1.50 (ddd, J
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= 14.2 Hz, 2.9 Hz, 2.9 Hz, 1H), 1.17-1.09 (m, 1H). C{1H} NMR (150 MHz, CDCl3): δ 203.9, 170.0, 144.7,
110.6, 104.1, 66.3, 63.7, 51.0, 48.0, 32.1, 26.3, 21.1. IR (cm-1): 2954 (m), 2924 (m), 2851 (m), 1765 (s),
1737 (s), 1008 (s). HRMS: Calculated for C12H14NaO5 ([M+Na]+): 261.0733. Found: 261.0754.
(3bR,7aR)-4,5,7,7a-Tetrahydrofuro[3',2':3,4]cyclopenta[1,2-c]pyran-8(3bH)-one,
(31).
Synthesized from 7a (0.014 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 50% EtOAc in hexanes to afford a yellow-brown oil (35.4 mg, 0.20 mmol, 71%
1
yield). TLC: Rƒ = 0.18, (33% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.79 (d, J = 1.7 Hz, 1H), 6.53
(d, J = 1.7 Hz, 1H), 4.24 (dd, J = 12.1 Hz, 3.6 Hz, 1H), 3.90 (dd, J = 12.1 Hz, 5.7 Hz, 1H), 3.75-3.70 (m, 1H),
3.60 (ddd, J = 11.2 Hz, 8.3 Hz, 4.1 Hz, 1H), 3.41 (ddd, J = 6.7 Hz, 6.7 Hz, 6.7 Hz, 1H), 3.03 (ddd, J = 5.9 Hz,
5.9 Hz, 3.7 Hz, 1H), 2.25 (dddd, J = 14.0 Hz, 6.5 Hz, 6.5 Hz, 4.1 Hz, 1H), 1.65 (dddd, J = 13.9 Hz, 6.7 Hz, 6.7
Hz, 4.8 Hz, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 187.9, 159.2, 154.7, 153.8, 109.3, 64.4, 64.3, 52.1, 29.5,
28.9. IR (cm-1): 2953 (m), 2854 (m), 1709 (s), 1429 (s). HRMS: Calculated for C10H10NaO3 ([M+Na]+):
201.0522. Found: 201.0527.
(3bR,7aR)-4,5,7,7a-Tetrahydrothieno[3',2':3,4]cyclopenta[1,2-c]pyran-8(3bH)-one,
(32).
Synthesized from 7b (0.028 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 33% EtOAc in hexanes to afford a yellow solid (mp = 83-87 °C) (26.5 mg, 0.14
mmol, 53% yield). TLC: Rƒ = 0.28, (33% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.92 (d, J = 4.8 Hz,
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1H), 7.08 (d, J = 4.8 Hz, 1H), 4.27 (dd, J = 12.1 Hz, 3.8 Hz, 1H), 3.91 (dd, J = 12.1 Hz, 5.8 Hz, 1H), 3.72-3.67
(m, 1H), 3.61-3.52 (m, 2H), 3.07 (ddd, J = 6.2 Hz, 6.2 Hz, 3.8 Hz, 1H), 2.24 (dddd, J = 14.1 Hz, 6.4 Hz, 6.4
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Hz, 3.8 Hz, 1H), 1.69-1.62 (m, 1H). C{1H} NMR (150 MHz, CDCl3): δ 196.4, 171.4, 140.9, 140.1, 123.0,
64.75, 64.70, 52.4, 33.8, 29.8. IR (cm-1): 2920 (m), 2851 (m), 1695 (s). HRMS: Calculated for C10H10NaO2S
([M+Na]+): 217.0294. Found: 217.0299.
(3bR,7aS)-3b,6,7,7a-Tetrahydrofuro[2',3':4,5]cyclopenta[1,2-c]pyran-8(4H)-one,
(35).
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Synthesized from 21 (0.014 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 50% EtOAc in hexanes to afford a yellow oil (31.2 mg, 0.18 mmol, 61% yield). TLC:
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Rf = 0.32, (50% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ 7.78 (s, 1H), 6.50 (s, 1H), 4.16 (dd, J =
11.6 Hz, 5.6 Hz, 1H), 3.82 (ddd, J = 10.5 Hz, 4.8 Hz, 4.8 Hz, 1H), 3.45 (ddd, J = 10.8 Hz, 10.8 Hz, 4.5 Hz,
1H), 3.40 (ddd, J = 6.3 Hz, 6.3 Hz, 6.3 Hz, 1H), 3.35 (dd, J = 11.6 Hz, 7.1 Hz, 1H), 3.17-3.13 (m, 1H), 2.23-
2.17 (m, 1H), 2.12-2.04 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 189.2, 156.0, 155.1, 153.7, 109.5, 68.9,
64.9, 49.1, 33.2, 23.5. IR (cm-1): 2922 (w), 2852 (w), 1699 (s). HRMS: Calculated for C10H10NaO3
([M+Na]+): 201.0522. Found: 201.0544.
(3bR,7aS)-3b,6,7,7a-Tetrahydrothieno[2',3':4,5]cyclopenta[1,2-c]pyran-8(4H)-one,
(36).
Synthesized from 22 (0.056 M in HFIP, 6.8 min exposure time) and purified via silica gel column
chromatography using 33% EtOAc in hexanes, then 50% EtOAc in hexanes, to afford a yellow-brown oil
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(35.6 mg, 0.18 mmol, 71% yield). TLC: Rf = 0.46, (50% EtOAc in hexanes). H NMR (600 MHz, CDCl3): δ
7.90 (d, J = 4.7 Hz, 1H), 7.04 (d, J = 4.7 Hz, 1H), 4.17 (dd, J = 11.9 Hz, 6.0 Hz, 1H), 3.81 (ddd, J = 10.4 Hz,
10.4 Hz, 4.7 Hz, 1H), 3.54 (ddd, J = 6.6 Hz, 6.6 Hz, 6.6 Hz, 1H), 3.39 (ddd, J = 11.0 Hz, 11.0 Hz, 4.3 Hz, 1H),
3.29 (dd, J = 11.9 Hz, 7.6 Hz, 1H), 3.19 (ddd, J = 6.8 Hz, 6.8 Hz, 3.9 Hz, 1H), 2.22 (dddd, J = 14.4 Hz, 4.0 Hz,
4.0 Hz, 4.0 Hz, 1H), 2.10-2.02 (m, 1H). 13C{1H} NMR (150 MHz, CDCl3): δ 197.6, 168.0, 140.6, 140.5, 123.2,
69.9, 65.2, 49.8, 37.1, 23.6. IR (cm-1): 2918 (w), 2849 (w), 1693 (m). HRMS: Calculated for C10H10NaO2S
([M+Na]+): 217.0294. Found: 217.0317.
(4aR,8aR)-4a,7,8,8a-Tetrahydrofuro[2',3':3,4]cyclopenta[1,2-c]pyran-4(5H)-one,
(38).
Synthesized from 7g (0.014 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 33% EtOAc in hexanes to afford an orange solid (mp = 51-55 °C) (38.8 mg, 0.22
mmol, 76% yield). TLC: Rƒ = 0.24, (33% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.53 (d, J = 1.7 Hz,
1H), 6.55 (d, J = 1.7 Hz, 1H), 4.26 (dd, J = 12.1 Hz, 3.6 Hz, 1H), 3.88 (dd, J = 12.1 Hz, 5.7 Hz, 1H), 3.73-3.68
(m, 1H), 3.60 (ddd, J = 11.6 Hz, 8.0 Hz, 4.2 Hz, 1H), 3.54 (ddd, J = 6.8 Hz, 6.8 Hz, 6.8 Hz, 1H), 3.11 (ddd, J =
6.0 Hz, 6.0 Hz, 3.9 Hz, 1H), 2.24 (dddd, J = 13.8 Hz, 6.7 Hz, 6.7 Hz, 4.5 Hz, 1H), 1.80 (dddd, J = 14.5 Hz, 7.5
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Hz, 7.5 Hz, 5.1 Hz, 1H). C{1H} NMR (150 MHz, CDCl3): δ 195.2, 184.6, 149.7, 127.2, 105.6, 64.1, 63.9,
53.2, 31.7, 26.5. IR (cm-1): 2957 (m), 2924 (s), 2853 (m), 1705 (m). HRMS: Calculated for C10H10NaO3
([M+Na]+): 201.0522. Found: 201.0525.
tert-Butyl
(3bR,7aS)-8-oxo-3b,4,6,7,7a,8-hexahydro-5H-furo[2',3':4,5]cyclopenta[1,2-
c]pyridine-5-carboxylate, (39). Synthesized from 24 (0.014 M in HFIP, 3.4 min exposure time) and
purified via silica gel column chromatography using 50% EtOAc in hexanes to afford a white solid (mp =
1
145-147 °C) (22.6 mg, 0.081 mmol, 45% yield). TLC: Rf = 0.39, (50% EtOAc in hexanes). H NMR (300
MHz, CDCl3): δ 7.78-7.75 (m, 1H), 6.56-6.51 (m, 1H), 3.72-3.63 (m, 2H), 3.46-3.38 (m, 1H), 3.27 (t, J = 6.5
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Hz, 2H), 3.10 (q, J = 6.1 Hz, 1H), 2.16-2.05 (m, 2H), 1.34 (s, 9H). C{1H} NMR (75 MHz, CDCl3): δ Note:
Small rotamer peaks shown in parentheses. 189.3, (189.1), 157.5, (156.8), (156.0), (155.7), 155.6, 154.9,
154.3, (154.1), 110.0, (109.6), 79.8, 49.8, 42.2, 41.1, (41.0), (40.5), 34.0, 28.5, 23.0, (22.8). IR (cm-1): 2975
(m), 2930 (m), 2881 (m), 1699 (s). HRMS: Calculated for C15H19NNaO4 ([M+Na]+): 300.1206. Found:
300.1235.
(3bR,7aS)-5-Tosyl-3b,4,5,6,7,7a-hexahydro-8H-furo[2',3':4,5]cyclopenta[1,2-c]pyridin-8-one,
(40). Synthesized from 25 (0.0070 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 50% EtOAc in hexanes to afford a light yellow solid (mp = 112-116 °C) (26.8 mg,
0.081 mmol, 58% yield). TLC: Rf = 0.42, (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.76 (d, J =
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1.8 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 7.0 Hz, 2H), 6.51 (d, J = 1.8 Hz, 1H), 3.77 (dd, J = 12.6 Hz,
5.3 Hz, 1H), 3.52-3.45 (m, 1H), 3.36 (ddd, J = 11.3 Hz, 5.6 Hz, 5.6 Hz, 1H), 3.10-2.88 (m, 3H), 2.41 (s, 3H),
2.16-1.98 (m, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 188.2, 156.1, 155.2, 154.2, 143.8, 134.5, 130.0, 127.4,
109.6, 49.4, 46.1, 42.6, 33.6, 22.7, 21.7. IR (cm-1): 2920 (w), 1703 (s), 1163 (s). HRMS: Calculated for
C17H17NNaO4S ([M+Na]+): 354.0771. Found. 354.0797.
tert-Butyl(3bR,7aR)-8-oxo-3b,4,5,7,7a,8-hexahydro-6H-furo[3',2':3,4]cyclopenta[1,2-
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c]pyridine-6-carboxylate, (41). Synthesized from 28 (0.0070 M in HFIP, 3.4 min exposure time) and
purified via silica gel column chromatography using 50% EtOAc in hexanes to afford a yellow oil (14.2
mg, 0.051 mmol, 45% yield). TLC: Rf = 0.31, (50% EtOAc in hexanes). 1H NMR (300 MHz, CDCl3): δ 7.80 (d,
J = 1.8 Hz, 1H), 6.52 (d, J = 1.8 Hz, 1H), 4.01-3.56 (m, 2H), 3.42-3.31 (m, 2H), 3.25-3.05 (m, 2H), 2.30-2.15
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(m, 1H), 1.95-1.83 (m, 1H), 1.44 (s, 9H). C{1H} NMR (75 MHz, CDCl3): Note: Small rotamer peaks shown
in parentheses. δ 188.1, 158.6, (155.43), 155.38, 154.5, (154.3), 109.5, 80.2, 53.1, (52.9), 40.5, 39.9,
(39.3), 30.3, 28.6, 25.1. IR (cm-1): 2975 (w), 2929 (w), 1704 (s). HRMS: Calculated for C15H19NNaO4
([M+Na]+): 300.1206. Found: 300.1211.
(3bR,7aR)-6-Tosyl-3b,4,5,6,7,7a-hexahydro-8H-furo[3',2':3,4]cyclopenta[1,2-c]pyridin-8-one,
(42). Synthesized from 29 (0.0070 M in HFIP, 3.4 min exposure time) and purified via silica gel column
chromatography using 50% EtOAc in hexanes to afford a yellow solid (decomposed at 135 °C) (23.3 mg,
0.070 mmol, 46% yield). TLC: Rf = 0.26, (50% EtOAc in hexanes). 1H NMR (600 MHz, CDCl3): δ 7.75 (s, 1H),
7.64 (d, J = 7.9 Hz, 2H), 7.29 (d, J = 7.8 Hz, 2H), 6.47 (s, 1H), 3.61-3.53 (m, 2H), 3.29-3.23 (m, 2H), 3.19-
13
3.12 (m, 2H), 2.42 (s, 3H), 2.21-2.14 (m, 1H), 1.74-1.67 (m, 1H). C{1H} NMR (150 MHz, CDCl3): δ 186.8,
158.1, 154.8, 154.4, 143.7, 134.7, 129.9, 127.6, 109.4, 52.3, 42.4, 42.0, 30.0, 26.4, 21.7. IR (cm-1): 2918
(w), 2850 (w), 1705 (m), 1162 (m). HRMS: Calculated for C17H17NNaO4S ([M+Na]+): 354.0771. Found:
354.0778.
Ring-opening50 of 31. Pyran 31 (203.1 mg, 1.14 mmol, 1.00 equiv) was dissolved in CH2Cl2 (8 mL),
the solution was cooled to 0 °C, and BBr3 (1.0 M in CH2Cl2, 1.71 mL, 1.71 mmol, 1.50 equiv) was added
dropwise. The solution was stirred at 0 °C for 15 min, and then warmed to room temperature. The
solution was stirred at room temperature for 1.0 h, during which time a light brown solid precipitated
and the solution turned opaque purple. Water (8 mL) was added, and the solution was stirred 15 min
before being transferred to a separatory funnel with CH2Cl2 (15 mL) and H2O (15 mL). The layers were
separated and the aqueous layer was extracted with CH2Cl2 (2 × 15 mL). The combined organic layers
were dried over magnesium sulfate and concentrated under reduced pressure. The crude product was
purified via silica gel column chromatography using 50% EtOAc in hexanes, affording 44 as a clear, light
yellow oil (35.4 mg, 0.14 mmol, 12% yield), and an inseparable mixture of the regioisomeric
bromoalcohol and enone 43 (ratio = 1.5 : 1.0, 173.6 mg). The mixture was dissolved in toluene (8 mL),
the solution was cooled to 0 °C, and DBU (0.19 mL, 1.25 mmol) was added dropwise. The mixture was
stirred 15 min before H2O (8 mL) was added, and the solution was transferred to a separatory funnel
with EtOAc (20 mL) and H2O (20 mL). The layers were separated and the aqueous layer was extracted
with EtOAc (2 × 10 mL). The combined organic layers were dried over magnesium sulfate and
concentrated under reduced pressure. The crude product was purified via silica gel column
chromatography using 50% EtOAc in CH2Cl2, affording enone 43 as a clear, colorless oil (100.6 mg, 0.56
mmol, 50% yield).
4-(2-Hydroxyethyl)-5-methylene-4,5-dihydro-6H-cyclopenta[b]furan-6-one, (48). TLC: Rf =
1
0.37, (50% EtOAc in CH2Cl2). H NMR (300 MHz, CDCl3): δ 7.76 (d, J = 1.7 Hz, 1H), 6.60 (d, J = 1.7 Hz, 1H),
6.23 (s, 1H), 5.55 (s, 1H), 3.89-3.76 (m, 3H), 2.21-2.10 (m, 1H), 1.91-1.79 (m, 1H), 1.71 (br s, 1H). 13C{1H}
NMR (75 MHz, CDCl3): δ 176.7, 156.6, 154.6, 153.4, 151.9, 118.4, 110.1, 60.6, 36.6, 34.7. IR (cm-1): 3392
(br), 3119 (w), 2928 (w), 1685 (s), 1636 (m), 1428 (m). HRMS: Calculated for C10H11O3 ([M+H]+):
179.0703. Found: 179.0698.
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(4R,5R)-4-(2-Bromoethyl)-5-(hydroxymethyl)-4,5-dihydro-6H-cyclopenta[b]furan-6-one, (49).
TLC: Rf = 0.67, (50% EtOAc in CH2Cl2). H NMR (300 MHz, CDCl3): δ 7.80 (d, J = 0.8 Hz, 1H), 6.57 (d, J = 0.9
1
Hz, 1H), 4.05 (ddd, J = 11.3 Hz, 5.8 Hz, 5.8 Hz, 1H), 3.93 (ddd, J = 10.9 Hz, 5.3 Hz, 5.3 Hz, 1H), 3.57 (t, J =
6.8 Hz, 2H), 3.26 (td, J = 7.4 Hz, 7.4 Hz, 2.3 Hz, 1H), 2.77 (td, J = 5.5 Hz, 5.4 Hz, 2.0 Hz, 1H), 2.49 (dd, J =
6.5 Hz, 4.7 Hz, 1H), 2.22 (q, J = 7.0 Hz, 2H). 13C{1H} NMR (75 MHz, CDCl3): δ 188.5, 158.5, 154.5, 154.0,
110.0, 62.5, 60.7, 37.2, 34.8, 30.9. IR (cm-1): 3408 (br), 3133 (w), 2927 (w), 1699 (s), 1432 (m). Unable to
acquire HRMS data; however, peaks at m/z = 258 and m/z = 260 with an approximately 1:1 ratio of
intensities were detected using low-resolution GC/MS.
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Scale-out synthesis of 8. In a round-bottom flask, aryl vinyl ketone 5a (1.50 g, 8.1 mmol) was
dissolved in acetic acid (152 mL, 0.056 M) and the solution was degassed with argon for 15 min. The
solution was then taken up in batches in a 60-mL syringe, which was placed on a syringe pump and
connected to FEP (fluorinated ethylene propylene) tubing (1.6 mm ID, 3.2 mm OD, 3.0 m length)
wrapped around a photochemical double-walled borosilicate glass immersion well housing a medium
pressure mercury vapor immersion lamp (450 W, 125-145 V, 3.6 A, 244.4 mm total length, 131.5 mm
arc).37 Ice-cooled water was flowed through the immersion well for the duration of the reaction. The
solution was pumped through the tubing at 53.3 mL/hour (6.8 min residence time) and collected in a
round-bottom flask. When all of the reaction solution had been pumped into the tubing, glacial acetic
acid (8 mL) was pumped through the tubing at the same flow rate until all solution containing the
reaction mixture was collected. The reaction mixture was diluted with ether (200 mL), and then washed
with a solution of saturated aqueous sodium bicarbonate (2 × 250 mL). The combined aqueous layers
were extracted with diethyl ether (2 × 250 mL), and the combined organic layers were washed with
brine (250 mL), dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The
crude reaction mixture was purified via silica gel column chromatography using 20% EtOAc in hexanes,
affording 8 (1.33 g, 7.54 mmol, 89%).
Acknowledgments
The authors are grateful to UNCW for start-up funds and a Cahill Award in support of this research. The
NSF Division of Chemistry provided grants through the Major Research Instrumentation Program for
mass spectrometry (CHE-1039784) and 600 MHz NMR facilities (CHE-0821552) in the UNC Wilmington
Department of Chemistry and Biochemistry. The authors also thank Dr. Michael Webb for his assistance
in recording mercury vapor lamp emission spectra and Dr. Shu-Yu (Aaron) Liao for his assistance with
acquisition of 2D NMR data.
Supporting Information
1H and 13C{1H} NMR spectra for compounds 5-49, UV emission spectra for medium pressure mercury
vapor lamp, and photo-Nazarov data tables (PDF)
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