Batch and Flow Synthesis of Pyrrolo[1,2-a]-quinolines via an Allene-Based Reaction Cascade

Article abstract of DOI:10.1021/acs.joc.5b01982

An efficient reaction cascade delivering a series of pyrrolo[1,2-a]quinolines bearing phosphonate or phosphine oxide moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a strategic [2,3]-sigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected pyrrolo[1,2-a]quinolines on multigram scale without any safety concerns due to the reaction's inherent exothermic profile.

Full text of DOI:10.1021/acs.joc.5b01982

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Article
Batch and Flow Synthesis of Pyrrolo[1,2-
a]quinolines via an Allene-based Reaction Cascade
Marcus Baumann, and Ian R. Baxendale
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01982 • Publication Date (Web): 19 Oct 2015
Downloaded from http://pubs.acs.org on October 20, 2015
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The Journal of Organic Chemistry
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Batch and Flow Synthesis of Pyrrolo[1,2-a]-quinolines via an
Allene-based Reaction Cascade
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Marcus Baumann, Ian R. Baxendale*
Department of Chemistry, University of Durham, South Road, DH1 3LE, Durham United Kingdom
KEYWORDS sigmatropic rearrangements, allenes, heterocycles, reaction cascades, flow chemistry.
ABSTRACT: An efficient reaction cascade delivering a series of pyrrolo[1,2ꢀa]quinolines bearing phosphonate or phosphine oxide
moieties is presented. This sequence exploits the in situ transformation of propargylic alcohols into transient allenes by means of a
strategic [2,3]ꢀsigmatropic rearrangement followed by trapping of the resulting allenes by an adjacent pyrrole ring. Furthermore, the
initial small scale batch process was successfully translated into a continuous flow process allowing efficient preparation of selected
pyrrolo[1,2ꢀa]quinolines on multigram scale without any safety concerns due to the reaction’s inherent exothermic profile.
Introduction
The efficient synthesis and functionalization of valuable heterocyclic architectures bearing different diversification sites constiꢀ
tutes one of the major challenges in modern medicinal chemistry in its aim to identify suitable scaffolds that can be used as potenꢀ
tial lead structures towards new bioactive molecules.1 Whilst approaches in the past have primarily focused on elaborating classic
heterocyclic systems (indoles, imidazoles, pyridines etc.) as core structures, the pressure imposed on modern medicinal chemists to
discover new drugꢀlike molecules means that new approaches are required in order to rapidly gain access to heterocyclic structures
covering underrepresented chemical space. The tricyclic pyrrolo[1,2ꢀa]quinoline system (Figure 1) represents such a scaffold that
has not been studied widely, likely due to limited robust synthetic strategies for its modular assembly. In addition, most of the reꢀ
ported methods require transition metal catalysis or strong Lewis acids to affect the cyclisation reaction,2 rendering these options
less amenable to simple and cheap scale up. Still, due to its embedded quinoline and indolizine substructures, which can be found in
numerous natural products and active pharmaceutical ingredients,3 structures based on the pyrrolo[1,2ꢀa]quinoline scaffold are preꢀ
disposed with drugꢀlike features.
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Figure 1: Structural motifs of pyrrolo[1,2ꢀa]quinolines as common features of bioactive molecules.
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We set out to design and develop a new synthetic strategy that would allow for the efficient preparation of a series of pyrrolo[1,2ꢀ
a]quinolines bearing a variety of different functional patterns. In addition, we intended to introduce different phosphorousꢀbased
functionalities which would serve a dual purpose: (1) as a means towards the synthesis effort and (2) as an important motif often
encountered in bioactive agents.4 Our synthetic strategy outlined in Scheme 1 is based on a reaction cascade that converts proparꢀ
gylic alcohols via a [2,3]ꢀsigmatropic rearrangement of the intermediate phosphites into transient allenes that are subsequently
trapped by an adjacent pyrrole nucleophile.
Scheme 1: Reaction cascade towards desired products and selected phosphonate containing bioactive compounds.
Results and Discussion
The conversion of propargylic alcohols into allenes bearing phosphine oxides or phosphonates via a [2,3]ꢀsigmatropic rearꢀ
rangements is a wellꢀestablished process5 and has been used recently to yield various heterocycles including indoles,6 benzofurans,7
pyrroles, 8 triazoles9 and chromene derivatives, here we report on the extension of this reaction into a new class of hererocyle.10
We initiated our study by devising the retrosynthetic strategy outlined in Scheme 2. As such the desired pyrrolo[1,2ꢀa]quinoline
products 1 were envisaged to arise from intermediate allenes 2 that in turn would be formed in situ from various propargylic alcoꢀ
hols 3 and chlorophosphine derivatives 4. The propargylic alcohols 3 would be accessed from a selection of substituted anilines 5
via a three step sequence consisting of regioselective iodination, PaalꢀKnorr pyrrole formation and a subsequent Sonogashira cross
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coupling reaction. This synthetic approach allows maximization of the functional components which can be introduced in to the
main framework using robust and efficient chemical transformations.
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Scheme 2: Retrosynthetic strategy towards 1.
Pleasingly it was found that a variety of anilines could be orthoꢀiodinated in high yield and regioselectivity when employing stoiꢀ
chiometric amounts of Nꢀiodosuccinimide (NIS) in the presence of acetic acid as solvent (Scheme 3). In cases where either diioꢀ
dinated byproducts or other regioisomers were formed, it was found that these were difficult to remove at this stage but that the
resulting mixtures could be used in the subsequent transformations without issue.
Scheme 3: Synthesis of substrates (20ꢀ50 mmol scale, aggregate yield over 3 steps).
Next, the conversion of the amino group of the iodoaniline intermediates into a pyrrole ring was carried out by treatment with
2,5ꢀdimethoxytetrahydrofuran in acetic acid at elevated temperatures (80 °C). The desired pyrrole derivatives 6 were generated
rapidly and reliably on synthetically useful scales (10ꢀ50 mmol) in a very efficient transformation. In order to furnish the correꢀ
sponding propargylic alcohols 3aꢀh, a standard protocol for Sonogashira cross coupling reactions using N,Nꢀdiisopropylamine as
base and PdCl2(PPh3)2 with CuBr/NaI as catalyst system was chosen and proved effective in delivering the key building blocks
needed in this study (see SI for further information). Importantly, this protocol tolerated the presence of less reactive chloride and
bromide substituents on the substrates thus enabling future derivatization efforts. At this stage chromatographic purification could if
required be used in order to remove any minor impurities generated in the preceding sequence.
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With a selection of different propargylic alcohols in hand we next turned our attention to studying their conversion to transient alꢀ
lene species mediated by a [2,3]ꢀsigmatropic rearrangement. For this purpose we decided to treat our substrates with two different
phosphine species, chlorodiphenylphosphine (4a) or diethyl chlorophosphite (4b), in the presence of triethylamine as base. At amꢀ
bient temperature rapid consumption of the propargylic alcohol starting material was observed by tlc when using either chloroform
or ethyl acetate as solvent, delivering the corresponding allene intermediates 2 that would subsequently be trapped by the adjacent
pyrrole ring. Typically, the desired tricyclic pyrrolo[1,2ꢀa]quinoline structure 1 would form within 2ꢀ8 h. It is interesting to note
that the allenes derived from chlorodiphenylphosphine (4a) underwent cyclisation considerably faster (2ꢀ3 h) than those derived
from diethyl chlorophosphite (4b, >4 h), whereas the nature of the substituent on the aromatic ring had little effect on the cyclisaꢀ
tion step. Overall, these results confirm the feasibility of using allenes as precursors towards more elaborate heterocyclic systems
that can be isolated in high yield after aqueous workꢀup and chromatographic purification (Scheme 4).
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ClPR2, NEt3,
CHCl3
or EtOAc,
rt, 1-8 h
+/- H+
R'
[2,3]
N
N
N
N
R'
R'
R'
PR2
O
OH
PR2
PR2
3a-h
3'a-h
2a-h
1a-j O
O
F
NO2
N
Br
N
N
Cl
N
P
N
P
Cl
N
F
F
Cl
P
Ph
Ph
P
Ph
Ph
P
Ph
Ph
Ph
Ph
Ph
Ph
O
O
O
O
O
1a, 78%
1e, 79%
1b, 81%
1c, 84%
1d, 86%
F
NO2
N
Br
N
N
Cl
N
N
Cl
N
F
F
Cl
P
OEt
1f, 73%
OEt
P
OEt
1j, 71%
OEt
P
OEt
OEt
P
OEt
OEt
P
OEt
OEt
O
O
O
O
O
1g, 79%
1h, 77%
1i, 70%
Scheme 4: Synthesis of tricyclic pyrrolo[1,2ꢀa]quinolines.
It was also shown that this rearrangement/cyclisation cascade could be extended in order to furnish the intriguing pyrrolo[1,2ꢀ
a][1,5]naphthyridine scaffold whose structure was confirmed by single crystal Xꢀray diffraction experiments (Figure 2).
Figure 2: Xꢀray structure of 1e (CHCl3 solvate; methyl group distorted).
We next evaluated the impact of introducing further substitution on the allene intermediate by utilizing propargylic alcohols 3fꢀh
as substrates in our cascade protocol. To this end, solutions of the alcohol substrates were treated again with either chlorodipheꢀ
nylphosphine (4a) or diethyl chlorophosphite (4b) in the presence of stoichiometric amounts of triethylamine. The intermediate
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tetrasubstituted allene species formed as expected, however, its subsequent conversion into the desired pyrrolo[1,2ꢀa]quinoline
structure did not occur even after prolonged periods of time (48 h) or at slightly elevated temperature (55 °C). As these tetrasubstiꢀ
tuted allenes were stable entities we decided to isolate and purify them in order to further study this unexpected outcome. As a conꢀ
sequence of their crystalline nature we were thus able to secure a single crystal Xꢀray structure of 2f allowing us to postulate the
reason behind their reluctance to cyclize (Figure 3).
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Figure 3: Xꢀray structure of 2f (one ethyl group distorted).
As expected, the proximal gemꢀdimethyl group is oriented perpendicular to the aryl and phosphite substituents on the distal part
of the allene. Consequently, this forces the pyrrole ring out of plane with respect to the aryl system in order to minimise steric hinꢀ
derance, resulting in a larger distance between the pyrrole and the central allene carbon and thus preventing the cyclization reaction.
We reasoned that it may still be possible to induce cyclization using higher temperatures which would overcome this barrier leading
to the formation of the desired pyrrolo[1,2ꢀa]quinolines bearing an isopropyl substituent.
Heating a selection of the crude allene species at 120 °C in a Biotage™ microwave reactor for a short period of time (1 h) quickꢀ
ly confirmed the viability of this approach by generating the desired products (Scheme 5). In the cases of phosphonates 1k, 1m and
1o a single aromatic product was formed, whereas for systems bearing the phosphine oxide motif a ~1 : 1 mixture of products 1l/1l’
(etc.) was obtained.11 Furthermore, the triethylammonium hydrochloride formed in the initial phosphorylation step appears to act as
a proton transfer catalyst as in its absence formation of the cyclized species was not observed.
ClPR2, NEt3,
CHCl3 or EtOAc,
rt, 2-8 h
MW, CHCl3
or EtOAc,
N
N
N
R'
R'
R'
120 oC, 1 h
OH
O
P
R
O
P
R
R
R
3f-h
2
1k-n
, isolable
F
F
F
F
N
N
N
N
P
F
F
F
F
O
P
O
P
O
O
P
R
R
Ph
Ph
OEt
Ph
Ph
EtO
2f
1k
1l
1l'
, R = OEt, 83%
, 83%
N
, 41%
N
, 37%
N
2f', R = Ph, 90%
N
NC
NC
NC
NC
O
P
O
P
O
P
R
R
O
P
Ph
OEt
Ph
Ph
EtO
Ph
2g
2g
, R = OEt, 90%
', R = Ph, 88 %
1m
1n
, 78%
', 32%
1n, 38%
N
N
N
N
Br
Br
Br
Br
O
P
O
P
O P
O
P
R
OEt
Ph
Ph
EtO
R
Ph
1p, 36%
Ph
1p', 40%
2h, R = OEt, 90%
2h'
1o, 79%
, R = Ph, 87%
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Scheme 5: Synthesis of pyrrolo[1,2ꢀa]quinolines via tetrasubstituted allenes.
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In order to further investigate the intricate balance between the specific substitution pattern on the propargylic alcohol and the reꢀ
sulting allene reactivity and final product distribution we decided to evaluate a number of further cases. As such a selection of proꢀ
pargylic substrates based on the pyrroloꢀ2,4ꢀdifluorobenzene scaffold were prepared using the aforementioned Sonogashira apꢀ
proach. Besides having either two hydrogens (table 1, entry 1) or two methyl groups (table 1, entry 2) in the propargylic position we
were thus able to study substrates possessing one methyl group and one hydrogen (table 1, entry 3) as well as one methyl group and
one phenyl ring (table 1, entry 4) as bulky substituents (Table 1).
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Table 1: Comparative study on the influence of steric bulk on the cyclisation process.
entry
substitution
pattern
allene
cyclisation
conditions
yielda and
stability
endo/ exo ratio
1
2
R1 = R2 = H
transient
stable
rt, 4 h
79%, n. a.
83%, 1 : 0
R1 = R2 = Me
MW, 120 °C,
1.5 h
3
4
R1 = H, R2 = Me
unstable
stable
rt, 12 h
85%, 1 : 0.7b
R1 = Me, R2 =
Ph
74%, 0.15 : 1d
MW, 120 °C,
2.5 hc
a
c
.
d
combined isolated yield; b exocyclic alkene has Zꢀgeometry; in the presence of 1.0 equiv. NEt3 HCl; d exocyclic alkene has
Eꢀgeometry.
Consistent with our expectations we observed the clean rearrangement of the propargylic substrates into the corresponding allene
structures upon treatment with diethyl chlorophosphite (4b) and triethylamine. Whilst the allene intermediate bearing one hydrogen
and one methyl group was shown to slowly undergo cyclisation at room temperature (table 1, entry 3), its derivative possessing a
phenyl group instead of the hydrogen required much more forcing conditions (table 1, entry 4). As such we further surmised that
trisubstituted allenes (table 1, entry 3) are capable of undergoing the cyclisation reaction towards the desired tricyclic products at
room temperature by minimizing steric interactions between the pendent group and the pyrrole ring. Finally, cyclisation of the steꢀ
rically most demanding tetrasubstituted allene (table 1, entry 4) did not occur under the microwave conditions previously estabꢀ
lished (table 1, entry 2), however, adding triethylammonium chloride as a proton transfer catalyst proved effective in forcing the
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cyclisation to occur under prolonged microwave radiation. As expected, the ratio of exoꢀ versus endocyclic alkene product would
for this substrate strongly favor the exocyclic structure.
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Having established that a variety of different pyrrolo[1,2ꢀa]quinolines can be prepared effectively through the intermediacy of
highly substituted allenes, we turned our attention towards translating this batch procedure into a continuous flow protocol. This
decision was driven by the expectation that such a flow procedure would be valuable as it would deliver the desired heterocyclic
products not only on gram scale, but also through a faster and cleaner process.12 Additionally, as we had commonly noted a temperꢀ
ature increase to ~40°C when performing the above reaction cascade in batch on small scales (1 mmol), we anticipated this to beꢀ
come more problematic when scaling up. We therefore wished to harness the benefits of continuous processing which renders imꢀ
provements through superior heat and mass transfer13 as well as improved safety profiles14 when compared to batch based scale up
approaches.
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We elected to use a VapourtecꢀEꢀseries flow system which was configured as shown in Scheme 6 so that two streams containing
mixtures of the starting materials would combine in a Tꢀpiece prior to entering into a heated flow coil in which the cascade reaction
would take place. Upon exiting the heated reactor the crude product stream would rapidly cool before being mixed with a quenchꢀ
ing stream (aqueous K2CO3) and the product being collected (Scheme 6).
Scheme 6: Flow reactor configuration.
Due to long term stability concerns regarding the chlorophosphine/phosphite (4a/4b) reagents in ethyl acetate, we opted to use
chloroform as the reaction solvent. Consequently, stock solution A was prepared by combining the propargylic alcohol substrate
(1.0 equiv., 1.0 M CHCl3) with triethylamine (1.3 equiv., 1.3 M CHCl3) and a second stock solution B was prepared from the chloꢀ
rophosphine/phosphite reagent (1.3 equiv., 1.3 M CHCl3).
Aiming to establish as to whether this flow approach would succeed in accelerating and improving the previous batch procedure,
we decided to study the conversion of substrates 3a, 3b and 3h into their corresponding pyrrolo[1,2ꢀa]quinoline derivatives (1f, 1b
and 1o). Starting with substrates 3a and 3b we were pleased to see their clean conversion into products 1f and 1b respectively,
when using a single heated reactor coil (10 mL internal volume) at slightly elevated temperature (80 °C) within a short residence
time of 1 h (table 2, entries 1 and 2). Compared to the previous batch experiments we noted a slightly cleaner and consequently
higher yielding reaction (see Scheme 4) which we ascribe to the better heat transfer in the Tꢀmixer leading to minimal side reacꢀ
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tions. Overall, this simple flow protocol enabled preparation of 1f and 1b continuously at a rate of 18 mmol/h allowing for the efꢀ
fective production of 8.3 g of 1f and 3.5 g of 1b as a proof of concept.
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2
3
4
5
6
7
Table 2: Results for continuous flow procedure.
8
9
entry
transforꢀ
mation
conditions
mmol/h
yield
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1
2
3
18
79%
85%
79%
3a → 1f
3b → 1b
3h →1o
flow, 80 °C, 1 h tRes
flow, 80 °C, 1 h tRes
18
batch, rt, 12 h, then MW
(1.5 h, 120 °C)
< 0.4
4
5
18
18
30ꢀ
3h →1o
3h →1o
flow, 80 °C, 0.5 h tRes
0.5 h at 120 °C
+
40%
60%
flow, 80 °C, 0.5 h tRes
0.5 h, UV (75 W), 80 °C
+
Having established a basic flow process we next turned our attention to the more challenging task of converting substrate 3h into
product 1o for which our previous batch efforts had indicated an inhibited cyclization step (table 2, entry 3). In analogy to the preꢀ
vious two flow sequences (table 2, entries 1 and 2) we realized the clean formation of allene intermediate 2h when using a single
coil reactor at 80 °C (0.5ꢀ1 h tRes), albeit without significant amounts of the desired cyclisation product 1o (<5%). We therefore addꢀ
ed a further coil reactor operating at a higher temperature (120 °C, 0.5 h tRes) downstream to the first in order to force the cyclization
step to occur. Although this setꢀup increased the formation of 1o to about 30ꢀ40% (table 2, entry 4), these results were not satisfacꢀ
tory as the crude product still contained the allene intermediate (2h, ~40%) and several unidentified side products (~20%).15,16 Anꢀ
ticipating that more forcing conditions would inevitably lead to the formation of more side products, we turned our attention to
employing a reactor configuration where a UVꢀflow reactor would be placed after the initial coiled reactor thus aiming to realize
the formation of allene intermediate 2h in the first reactor followed by its conversion into 3h facilitated in the UVꢀflow reactor. The
use of a photochemical activation of the allene portion was inspired by reports in the literature describing the benefits of triggering
reactions of allenes mediated by light.17 Using the aforementioned Vapourtec Eꢀseries flow system in conjunction with its UVꢀflow
reactor unit we were able to quickly screen a number of different conditions with respect to lamp power settings (65ꢀ140 W), temꢀ
perature of the UVꢀflow reactor (20ꢀ85 °C) as well as different light filters (see SI for full information). Upon further experimentaꢀ
tion it became apparent that this combination of a thermal coiled reactor with a second UV reactor was beneficial increasing the
conversion of 3h into 1o to the region of ~60% with smaller amounts of intermediate 2h (20%) and few side products being present
(table 1, entry 5). Although conditions for quantitative formation of 1o were not identified for this specific substrate, flow chemical
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processing was established as a valuable means to either continuously prepare allene intermediate 2h or pyrrolo[1,2ꢀa]quinoline 1o
allowing to generate multigram quantities (5ꢀ10 g) of either species within a single working day. Furthermore, a simpler flow setꢀup
utilizing only one coiled reactor had established a continuous process for the production of pyrrolo[1,2ꢀa]quinolines 1f and 1b with
a throughput of 18 mmol/h, which would not have been possible with the initially established batch procedure due to the exotherꢀ
mic reaction profile observed for small scale reactions (1ꢀ4 mmol, temperature rise by >20 °C).
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In conclusion, we have developed an efficient reaction sequence converting simple propargylic alcohols in the presence of differꢀ
ent chlorophosphine and phosphite species into a selection of tricyclic pyrrolo[1,2ꢀa]quinolines. This new reaction cascade proꢀ
ceeds through the intermediacy of highly substituted allenes demonstrating their value as reactive intermediates towards the conꢀ
struction of important yet underrepresented heterocyclic architectures. Furthermore, we extended on the initial small scale batch
procedure by devising an efficient continuous flow protocol enabling the production of selected products at mesoscale (18 mmol/h),
providing gram quantities of these heterocyclic entities for future studies regarding chemical modifications as well as biological
evaluations.
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EXPERIMENTAL SECTION
In a general procedure, the desired aniline derivative (5, 50 mmol, 1.0 equiv.) was dissolved in glacial acetic acid (10 mL) and combined
with Nꢀiodosuccinimide (50 mmol, 1.0 equiv.). The resulting reaction mixture was stirred at room temperature and monitored by 1H NMR
spectroscopy until complete conversion of the substrate was achieved (typically 2ꢀ6 h). The crude reaction product was then neutralized by
pouring into a saturated aqueous solution of K2CO3, followed by extraction using EtOAc. The combined organic layers were dried over
anhydrous Na2SO4, filtered and evaporated using a rotary evaporator. The iodinated aniline products were typically isolated as black oils
and used directly in the next step.
In a general procedure, to the crude iodoaniline product (25 mmol, 1.0 equiv.) dissolved in glacial acetic acid (10 mL) was added 2,5ꢀ
dimethoxytetrahydrofuran (30 mmol, 1.2 equiv.). The resulting mixture was heated at 80°C until full conversion of the starting material
into the desired pyrrole derivative was accomplished (monitored by 1H NMR spectroscopy; typically 1ꢀ4 h). After cooling to room temperꢀ
ature, the crude mixture was neutralized by pouring into saturated aqueous K2CO3, followed by extraction with EtOAc, drying of the comꢀ
bined organic layers over anhydrous Na2SO4 and evaporation of the volatiles. The desired products (6) were isolated as dark colored solids
and used directly in the next step.
In a general procedure, to a solution of the aryl iodide substrate (6, 10 mmol, 1.0 equiv.) in dry THF (8 mL) was added HNiPr2 (12 mmol,
1.2 equiv.). To this solution either propargyl alcohol (12 mmol, 1.2 equiv.) or 2ꢀmethylꢀ3ꢀbutynꢀ2ꢀol (12 mmol, 1.2 equiv.) were added
followed by addition of PdCl2(PPh3)2 (0.3 mmol), CuBr (0.5 mmol) and NaI (0.5 mmol). The resulting reaction mixture was stirred at 50°C
for 4ꢀ6 h until complete consumption of the starting material was observed by TLC. The reaction mixture was filtered over a plug of silica
before aqueous extraction with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated to yield
the crude product. Silica gel chromatography (10ꢀ20% EtOAc/hexanes) was subsequently used to yield clean product (3aꢀj).
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3-(5-Chloro-2-(1H-pyrrol-1-yl)phenyl)prop-2-yn-1-ol, (3a): brown solid, 75% yield (4.3 g on 25 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 7.50 (1H, d, J = 2.4 Hz), 7.34 (1H, dd, J = 8.6, 2.4 Hz), 7.22 (1H, d, J = 8.6 Hz), 7.04 (2H, t, J = 2.2 Hz),
6.33 (2H, t, J = 2.2 Hz), 4.36 (2H, s), 2.01 (1H, s). 13C NMR (101 MHz, CDCl3) δ 140.7 (C), 133.3 (CH), 131.9 (C), 129.6 (CH), 126.1
(CH), 121.7 (2CH), 118.9 (C), 109.7 (2CH), 93.1 (C), 81.3 (C), 51.4 (CH2). IR (neat, cmꢀ1) 3448 (broad), 1739 (w), 1496 (s), 1389 (m),
1329 (m), 1115 (m), 1069 (m), 1018 (s), 920 (m), 738 (s). LCꢀMS (ESI) m/z = 231.9 (M+H). HRꢀMS (TOF ES+) calculated for
C13H11NOCl 232.0529, found 232.0526 (ꢁ = ꢀ1.3 ppm). Melting range: 78.3 ꢀ 81.1 °C.
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3-(4-Chloro-5-fluoro-2-(1H-pyrrol-1-yl)phenyl)prop-2-yn-1-ol, (3b): yellow oil, 77% yield (4.8 g on 25 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.37 (1H, d, J = 6.7 Hz), 7.30 (1H, d, J = 8.9 Hz), 7.01 (2H, t, J = 2.2 Hz), 6.37 – 6.31 (2H, m), 4.36 (2H,
s), 2.18 (1H, s). 13C NMR (101 MHz, CDCl3) δ 155.9 (CF, d, J = 250 Hz), 138.9 (C, d, J = 3 Hz), 127.2 (CH), 122.1 (C, d, J = 19 Hz),
121.8 (2CH), 120.8 (CH, d, J = 24 Hz), 117.6 (C, d, J = 9 Hz), 109.9 (2CH), 93.6 (C), 80.6 (C, d, J = 2 Hz), 51.3 (CH2). 19F NMR (376
MHz, CDCl3) δ ꢀ117.62 (s). IR (neat, cmꢀ1) 3326 (broad), 1738 (w), 1492 (s), 1391 (m), 1273 (m), 1181 (s), 1069 (s), 1025 (s), 884 (s),
719 (s), 601 (m). LCꢀMS (ESI) m/z = 250.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C13H10NOFCl 250.0435, found 250.0440 (ꢁ = 0.5
ppm).
3-(3,5-Difluoro-2-(1H-pyrrol-1-yl)phenyl)prop-2-yn-1-ol, (3c): brown oil, 80% yield (4.7 g on 25 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.04 (1H, ddd, J = 8.4, 2.8, 1.7 Hz), 6.96 (1H, ddd, J = 9.7, 8.2, 2.9 Hz), 6.86 (2H, q, J = 1.9 Hz), 6.33
(2H, t, J = 2.1 Hz), 4.30 (2H, d, J = 6.1 Hz), 1.91 (1H, t, J = 6.1 Hz). 13C NMR (101 MHz, CDCl3) δ 160.6 (CF, dd, J = 250, 13 Hz),
157.3 (CF, dd, J = 253, 13 Hz), 127.5 (C, m), 123.1 (C, dd, J = 12, 3 Hz), 122.6 (2CH, d, J = 2 Hz), 115.3 (CH, dd, J = 24, 4 Hz), 109.2
(2CH), 105.6 (CH, dd, J = 26, 25 Hz), 93.9 (C), 80.3 (C, m), 51.3 (CH2). 19F NMR (CDCl3, 367 MHz) δ (s) ꢀ110.11 (d, J = 7.4 Hz), ꢀ
117.74 (d, J = 7.4 Hz). IR (neat, cmꢀ1) 3341 (broad), 3081 (w), 1597 (m), 1505 (s), 1439 (m), 1310 (m), 1196 (m), 1134 (s), 1067 (s), 1000
(s), 858 (s), 723 (s), 597 (m). LCꢀMS (ESI) m/z = 234.6 (M+H). HRꢀMS (TOFꢀES+) calculated for C13H10NOF2 234.0730, found
234.0733 (ꢁ = 1.3 ppm).
3-(5-Chloro-3-nitro-2-(1H-pyrrol-1-yl)phenyl)prop-2-yn-1-ol, (3d): yellow oil, 71% yield (3.9 g on 20 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.77 (1H, d, J = 2.4 Hz), 7.69 (1H, d, J = 2.4 Hz), 6.74 (2H, app t, J = 2.0 Hz), 6.34 (2H, app t, J = 2.0 Hz),
4.31 (3H, s), 1.66 (1H, br s). 13C NMR (101 MHz, CDCl3) δ 147.6 (C), 135.8 (CH), 134.1 (C), 133.9 (C), 125.4 (C), 124.2 (CH), 122.2
(2CH), 110.5 (2CH), 95.5 (C), 79.1 (C), 51.2 (CH2). IR (neat, cmꢀ1) 3349 (broad), 3076 (w), 1540 (s), 1497 (s), 1355 (s), 1171 (m), 1098
(m), 1046 (s), 922 (m), 723 (s), 692 (s), 519 (s). LCꢀMS (ESI) m/z = 277.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C13H10N2O3Cl
277.0380, found 277.0374 (ꢁ = ꢀ2.2 ppm).
3-(5-Bromo-(1H-pyrrol-1-yl)pyridine-2-yl)prop-2-yn-1-ol, (3e): yellow solid, 70% yield (4.8 g on 20 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 8.57 (1H, d, J = 2.0 Hz), 7.81 (1H, d, J = 2.0 Hz), 7.09 (2H, app t, J = 2.4 Hz), 6.37 (2H, app t, J = 2.4 Hz),
4.44 (2H, s), 1.83 (1H, br s). 13C NMR (101 MHz, CDCl3) δ 148.6 (CH), 139.4 (C), 135.1 (C), 134.8 (CH), 121.4 (2CH), 120.1 (C), 111.0
(2CH), 93.4 (C), 81.9 (C), 51.5 (CH2). IR (neat, cmꢀ1) 3252 (m), 3044 (w), 1571 (m), 1487 (m), 1112 (m), 1065 (m), 1029 (m), 934 (m),
794 (w), 721 (s), 609 (m). LCꢀMS (ESI) m/z = 277.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C12H10N2OBr 276.9976, found 276.9982
(ꢁ = 2.2 ppm). Melting point: 115 °C (decomposition).
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4-(3,5-Difluoro-2-(1H-pyrrol-1-yl)phenyl)-2-methylbut-3-yn-2-ol, (3f) yellow oil, 76% yield (2.0 g on 10 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.01 (1H, ddd, J = 8.4, 2.8, 1.7 Hz), 6.94 (1H, ddd, J = 9.7, 8.3, 2.8 Hz), 6.84 (2H, td, J = 2.2, 1.3 Hz), 6.33
(2H, t, J = 2.2 Hz), 2.34 (1H, s), 1.45 (6H, s). 13C NMR (101 MHz, CDCl3) δ 160.6 (CF, dd, J = 250, 13 Hz), 157.3 (CF, dd, J = 253, 13
Hz), 127.6 (C, dd, J = 13, 4 Hz), 123.6 (C, dd, J = 12, 3 Hz), 122.6 (2CH, d, J = 1 Hz), 114.8 (CH, dd, J = 24, 4 Hz), 109.2 (2CH), 105.3
(CH, dd, J = 26, 25 Hz), 100.4 (C), 76.9 (C, dd, J = 5, 3 Hz), 65.3 (C), 30.7 (2CH3). 19F NMR (CDCl3, 367 MHz) δ ꢀ110.17 (d, J = 7.4
Hz), ꢀ117.81 (d, J = 7.4 Hz). IR (neat, cmꢀ1) 3368 (broad), 2983 (w), 1592 (m), 1507 (s), 1439 (m), 1222 (m), 1128 (s), 1069 (m), 1016
(m), 999 (s), 951 (m), 859 (m), 722 (s), 617 (m). LCꢀMS (ESI) m/z = 284.3 (M+Na). HRꢀMS (TOFꢀES+) calculated for C15H14NOF2
262.1043, found 262.1055 (ꢁ = 4.6 ppm).
3-(3-Hydroxy-3-methylbut-1-yn-1-yl)-4-(1H-pyrrol-1-yl)benzonitrile, (3g): white solid, 77% yield (3.8 g on 20 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.81 (1H, d, J = 2.0 Hz), 7.63 (1H, dd, J = 8.4, 2.0 Hz), 7.39 (1H, d, J = 8.4 Hz), 7.17 – 7.12 (2H, m), 6.36
(2H, t, J = 2.2 Hz), 1.97 (1H, s), 1.55 (6H, s). 13C NMR (101 MHz, CDCl3) δ 145.1 (C), 137.8 (CH), 132.6 (CH), 125.1 (CH), 121.3
(2CH), 118.2 (C), 117.5 (C), 110.6 (2CH), 109.9 (C), 100.6 (C), 77.5 (C), 65.6 (C), 30.8 (2CH3). IR (neat, cmꢀ1) 3451 (m), 2981 (w), 2239
(m), 1598 (m), 1502 (s), 1393 (m), 1335 (s), 1061 (m), 922 (m), 913 (m), 837 (m), 733 (s), 618 (m). LCꢀMS (ESI) m/z = 273.1 (M+Na).
HRꢀMS (TOFꢀES+) calculated for C16H14N2ONa 273.1004, found 273.1004 (ꢁ = 0.0 ppm). Melting range: 122.0 ꢀ 123.1 °C.
4-(5-Bromo-2-(1H-pyrrol-1-yl)phenyl)-2-methylbut-3-yn-2-ol, (3h): yellow oil, 78% yield (11.7 g on 50 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.62 (1H, d, J = 2.3 Hz), 7.46 (1H, dd, J = 8.6, 2.3 Hz), 7.14 (1H, d, J = 8.5 Hz), 7.05 – 6.99 (2H, m), 6.34
– 6.28 (2H, m), 2.55 (1H, s), 1.51 (6H, s). 13C NMR (101 MHz, CDCl3) δ 141.2 (C), 136.0 (CH), 132.3 (CH), 126.2 (CH), 121.6 (2CH),
119.5 (C), 119.3 (C), 109.6 (2CH), 99.7 (C), 77.9 (C), 65.4 (C), 30.8 (2CH3). IR (neat, cmꢀ1) 3371 (broad), 2980 (w), 1496 (s), 1328 (m),
1162 (m), 1108 (m), 1064 (m), 964 (m), 926 (s), 910 (m), 818 (m), 723 (s), 550 (m). LCꢀMS (ESI) m/z = 325.9 (M+Na). HRꢀMS (TOFꢀ
ES+) calculated for C15H14NOBrNa 326.0166, found 326.0177 (ꢁ = ꢀ3.4 ppm).
4-(3,5-Difluoro-2-(1H-pyrrol-1-yl)phenyl)but-3-yn-ol, (3i): brown oil, 79% yield (4.9 g, on 25 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.02 (1H, ddd, J = 8.4, 2.8, 1.7 Hz), 6.95 (1H, ddd, J = 9.7, 8.2, 2.8 Hz), 6.84 (2H, td, J = 2.2, 1.3 Hz), 6.38
– 6.29 (2H, m), 4.55 (1H, q, J = 6.6 Hz), 2.00 (1H, s), 1.39 (3H, d, J = 6.6 Hz). 13C NMR (101 MHz, CDCl3) δ 160.6 (CF, dd, J = 250, 13
Hz), 157.3 (CF, dd, J = 253, 13 Hz), 127.5 (C, dd, J = 13, 4 Hz), 123.3 (C, dd, J = 12, 3 Hz), 122.6 (2CH, d, J = 2 Hz), 115.0 (CH, dd, J =
24, 4 Hz), 109.2 (2CH), 105.4 (CH, dd, J = 26, 25 Hz), 97.5 (C), 78.7 (C, dd, J = 5, 3 Hz), 58.5 (CH), 23.6 (CH3). 19F NMR (CDCl3, 367
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MHz) δ ꢀ110.14 (d, J = 7.4 Hz), ꢀ117.79 (d, J = 7.4 Hz). IR (neat, cmꢀ1) 3329 (broad), 2985 (w), 1616 (m), 15944 (m), 1508 (s), 1439 (m),
1308 (m), 1138 (s), 1118 (s), 1068 (s), 1009 (s), 859 (m), 724 (s), 617 (m), 598 (m). LCꢀMS (ESI) m/z = 248.0 (M+H). HRꢀMS (TOFꢀ
ES+) calculated for C14H12NOF2 248.0887, found 248.0911 (ꢁ = 4.7 ppm).
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1H NMR (400 MHz, CDCl3) δ 7.45 – 7.41 (2H, m), 7.36 – 7.27 (3H, m), 7.09 (1H, ddd, J = 8.4, 2.8, 1.7 Hz), 6.97 (1H, ddd, J = 9.6, 8.2,
2.8 Hz), 6.85 (2H, dt, J = 2.2, 1.1 Hz), 6.37 – 6.34 (2H, m), 2.46 (1H, s), 1.72 (3H, s). 13C NMR (101 MHz, CDCl3) δ 160.8 (CF, dd, J =
250, 13 Hz), 157.5 (CF, dd, J = 253, 13 Hz), 144.5 (C), 128.3 (2CH), 127.8 (CH), 127.6 (C, dd, J = 13, 5 Hz), 124.9 (2CH), 123.6 (C, dd, J
= 12, 3 Hz), 122.6 (2CH, d, J = 1 Hz), 115.0 (CH, dd, J = 24, 4 Hz), 109.4 (2CH), 105.5 (CH, dd, J = 26, 25 Hz), 98.8 (C), 79.5 (C, dd, J =
5, 3 Hz), 70.2 (C), 32.6 (CH3). 19F NMR (CDCl3, 367 MHz) δ ꢀ109.81 (d, J = 7.4 Hz), ꢀ117.60 (d, J = 7.4 Hz). IR (neat, cmꢀ1) 3384
(broad), 1591 (m), 1508 (s), 1438 (m), 1310 (m), 1128 (s), 1069 (s), 1016 (s), 997 (m), 850 (m), 764 (m), 725 (s), 6998 (s), 610 (m). LCꢀ
MS (ESI) m/z = 346.1 (M+Na). HRꢀMS (TOFꢀES+) calculated for C20H15NOF2Na 346.1019, found 346.1010 (ꢁ = ꢀ2.6 ppm).
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In a general batch procedure, propargylic alcohol 3aꢀj (1 mmol, 1.0 equiv.) was dissolved in chloroform (2 mL, 0.5 M) and combined with
triethylamine (1.3 mmol, 1.3 equiv.). To this mixture either chlorodiphenylphosphine or diethyl chlorophosphite (1.3 mmol, 1.3 equiv.)
was added carefully at room temperature avoiding temperature increase above 30 °C. The crude reaction mixture was stirred at room temꢀ
perature and reaction progress was monitored by tlc. In case of primary propargylic alcohols (R1 = H) full conversion of the substrate to the
desired product 1 was realized within 3ꢀ8 h, whereas for substrates with R1 = Me conversion of the intermediate allene 2 to 1 did not occur
at room temperature within 24 h. In either case the crude reaction mixture was quenched by adding excess aqueous K2CO3 solution folꢀ
lowed by aqueous extraction (3x 10 mL water). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated
to dryness using a rotary evaporator. Purification of the crude products was accomplished by silica column chromatography using EtOAc
(10ꢀ20%) and hexanes as solvent system allowing to isolate clean pyrrolo[1,2ꢀa]quinolines (1) or allenes (2).
In order to convert tetrasubstituted allenes 2 into the corresponding pyrrolo[1,2ꢀa]quinolines, the crude reaction mixtures were transferred
into a microwave vial (typically 5 mL volume), capped and heated at 110 °C in a Biotage microwave reactor for 90 minutes. Following the
same workꢀup and purification procedure outlined above allowed isolation of the pure cyclisation products.
For the continuous flow procedure, two stock solutions containing the propargylic alcohol 3a,c,h (1 equiv., 1.0 M) and NEt3 (1.3 equiv.) in
chloroform (stock solution A) and the chlorodiphenylphosphine or diethyl chlorophosphite reagent (1.3 equiv., 1.0 M in chloroform, stock
solution B) were prepared. Using a Vapourtec MedChem flow system streams of these two stock solutions were pumped at individual flow
rates of 0.3 mL/min. After mixing in a Tꢀpiece the combined stream was directed into two subsequent reactor coils (PTFE, 10 mL volume
each) maintained at 80 °C. After exiting these flow reactor coils a stream containing saturated aqueous K2CO3 solution was mixed with the
crude reaction stream in order to quench the reaction prior to passing through a backꢀpressure regulator (75 psi). The product was collected
in a separating funnel and workꢀup and purification was accomplished as described in the above batch scenario.
This setꢀup was used to prepare 1f (from 3a), 1b (from 3c) and 2h (from 3h) with a total flow path length (reactor coils and tubing) of 25
mL at a combined flow rate of 0.6 mL/min corresponding to a residence time of 41.7 minutes and a general throughput of 18 mmol subꢀ
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strate per hour. Starting from 30 mmol 3a yielded 23.7 mmol of purified 1f (79% yield, 8.32 g), 10 mmol 3c yielded 8.5 mmol purified 1b
(85%, 3.54 g) and at a reactor temperature of 50 °C 10 mmol 3h yielded 9.0 mmol purified 2h (90% yield, 3.70 g).
Upon increasing the temperature of the second reactor coil to 120 °C whilst leaving the first one at 50 °C substrate 3h was converted into
~35% 1o together with 40% 2h and several side products (10 mmol scale experiment). Additionally, when using a first reactor coil at 50
°C followed by a subsequent UVꢀphotoreactor coil (75 W power, 75ꢀ80 °C temperature) substrate 3h was converted to 60% 1o, 20% 2h as
well as ~15% side products (10 mmol scale experiment).
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(7-Chloro-4-methylpyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1a):3.2 g (78%, 10 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.36 (1H, d, J = 2.4 Hz), 7.90 (1H, dd, J = 1.2, 2.8 Hz), 7.70ꢀ7.79 (5H, m), 7.48ꢀ7.53 (2H, m), 7.41ꢀ7.47
(4H, m), 7.30 (1H, dd, J = 2.0, 8.8 Hz), 6.82 (1H, dd, J = 3.2, 4.0 Hz), 6.75 (1H, dd, J = 0.8, 4.0 Hz), 2.30 (3H, d, J = 1.6 Hz). 13C NMR
(101 MHz, CDCl3) δ 139.1 (C, d, J = 9 Hz), 135.1 (2C, d, J = 104 Hz), 131.8 (2CH, d, J = 3 Hz), 131.5 (2x2CH, d, J = 10 Hz), 131.3 (C,
d, J = 13 Hz), 130.5 (C, d, J = 9 Hz), 128.9 (2x2CH, J = 12 Hz), 128.8 (C), 128.5 (CH, d, J = 4 Hz), 127.3 (CH), 125.2 (C, d, J = 10 Hz),
115.5 (CH), 114.8 (CH), 113.9 (CH), 113.8 (C, d, J = 105 Hz), 106.3 (CH), 19.1 (CH3, d, J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 30.00
(s). IR (neat, cmꢀ1) 3057 (w), 1478 (m), 1437 (m), 1406 (m), 1171 (m), 1116 (m), 721 (s), 693 (s), 516 (s). LCꢀMS (ESI) m/z = 416.0
(M+H). HRꢀMS (TOFꢀES+) calculated for C25H20NOPCl 416.0971, found 416.0973 (ꢁ = 0.5 ppm).
(7,9-Difluoro-4-methylpyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1b): 3.4 g (81%, 10 mmol scale).
1H NMR (600 MHz, CDCl3) δ 8.29 (1H, s), 8.14 (1H, d, J = 11.4 Hz), 7.70ꢀ7.78 (4H, m), 7.49ꢀ7.55 (2H, m), 7.43ꢀ7.47 (4H, m), 6.94 (1H,
ddd, J = 2.4, 7.2, 13.2 Hz), 6.82 (1H, m), 6.80 (1H, m), 2.23 (3H, d, J = 1.8 Hz). 13C NMR (150 MHz, CDCl3) δ 156.8 (CF, dd, J = 243,
13 Hz), 152.5 (CF, ddd, J = 249, 13, 2 Hz), 139.7 (C, d, J = 9 Hz), 134.8 (2CP, d, J = 105Hz), 131.9 (2CH, d, J = 3 Hz), 131.5 (C, d, J =
12 Hz), 131.4 (2x2CH, d, J = 10 Hz), 128.9 (2x2CH, d, J = 12 Hz), 127.6 (C, td, J = 11, 3 Hz), 121.0 (CH, d, J = 23 Hz), 119.0 (C, td, J =
9, 3 Hz), 113.6 (CH, d, J = 5 Hz), 113.4 (CP, d, J = 106 Hz), 110.4 (CH, dt, J = 26, 4 Hz), 106.1 (CH, d, J = 1 Hz), 103.0 (CH, dd, J = 28,
25 Hz), 19.3 (CH3, d, J = 6 Hz). 31P NMR (CDCl3, 162 MHz) δ 30.30 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.0 (d, J = 18 Hz), ꢀ118.6
(d, J = 18 Hz). IR (neat, cmꢀ1) 3057 (w), 1629 (m), 1593 (m), 1472 (m), 1436 (m), 1415 (m), 1363 (m), 1172 (m), 1116 (s), 1045 (s), 721
(s), 694 (s), 541 (s). LCꢀMS (ESI) m/z = 417.7 (M+H). HRꢀMS (TOFꢀES+) calculated for C25H19NOPF2 418.1172, found 418.1166 (ꢁ =
ꢀ1.4 ppm).
(8-Chloro-7-fluoro-4-methylpyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1c): 3.6 g (84%, 10 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.48 (1H, d, J = 12.0 Hz), 7.90 (1H, dd, J = 1.2, 6.8 Hz), 7.85ꢀ7.87 (1H, m), 7.70ꢀ7.78 (4H, m), 7.55ꢀ7.59
(2H, m), 7.44ꢀ7.51 (4H, m), 6.85 (1H, dd, J = 2.8, 3.6 Hz), 6.75 (1H, dd, J = 1.2, 4.0 Hz), 2.20 (3H, d, J = 1.6 Hz). 13C NMR (101 MHz,
CDCl3) δ 153.7 (CF, d, J = 244 Hz), 138.5 (C, d, J = 9 Hz), 134.7 (2CP, d, J = 105 Hz), 132.0 (2CH, d, J = 3 Hz), 131.5 (2x2CH, d, J = 10
Hz), 131.2 (C, d, J = 14 Hz), 129.0 (2x2CH, d, J = 12 Hz), 124.1 (C, d, J = 8 Hz), 124.0 (C, d, J = 10 Hz), 120.4 (C, d, J = 21 Hz), 116.1
(C, dd, J = 26, 4 Hz), 115.8 (CH), 114.9 (CH), 114.1 (CH), 113.6 (CP, dd, J = 3, 101 Hz), 106.5 (CH), 19.2 (CH3, d, J = 6 Hz). 31P NMR
(CDCl3, 162 MHz) δ 30.58 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ120.0 (s). IR (neat, cmꢀ1) 2932 (w), 1436 (m), 1410 (m), 1165 (m), 1116
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(m), 844 (m), 715 (s), 690 (s), 622 (s), 545 (s), 526 (s), 513 (s). LCꢀMS (ESI) m/z = 434.3 (M+H). HRꢀMS (TOFꢀES+) calculated for
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C25H19NOPClF 434.0877, found 434.0872 (ꢁ = 1.2 ppm).
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(7-Chloro-4-methyl-9-nitropyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1d): 2.0 g (86%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.81 (1H, d, J = 2.0 Hz), 7.70ꢀ7.80 (4H, m), 7.54ꢀ7.60 (3H, m), 7.46ꢀ7.53 (4H, m), 7.40ꢀ7.44 (1H, m),
6.82ꢀ6.89 (2H, m), 2.24 (3H, d, J = 1.2 Hz). 13C NMR (101 MHz, CDCl3) δ 140.8 (C), 140.5 (C, d, J = 11 Hz), 134.4 (2C, d, J = 104 Hz),
132.3 (C, d, J = 13 Hz), 132.2 (2CH, d, J = 3 Hz), 131.7 (CH, d, J = 4 Hz), 131.4 (2x2CH, d, J = 10 Hz), 129.1 (2x2CH, d, J = 13 Hz),
128.2 (C, d, J = 11 Hz), 128.0 (C), 122.5 (CH), 122.0 (C, d, J = 8 Hz), 119.2 (CH), 115.3 (CH), 113.5 (C, d, J = 104 Hz), 107.6 (CH), 19.5
(CH3, d, J = 6 Hz). 31P NMR (CDCl3, 162 MHz) δ 30.06 (s). IR (neat, cmꢀ1) 3055 (w), 1529 (m), 1438 (m), 1364 (m), 1172 (s), 1114 (m),
948 (m), 751 (m), 719 (s), 691 (s), 519 (s). LCꢀMS (ESI) m/z = 460.9 (M+H). HRꢀMS (TOFꢀES+) calculated for C25H19N2O3PCl
461.0822, found 461.0814 (ꢁ = 1.7 ppm).
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(2-Bromo-6-methylpyrrolo[1,2-a][1,5]naphthyridin-5-yl)diphenyl phosphine oxide, (1e): 1.8 g (79%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.13 (1H, app t, J = 2.0 Hz), 8.11 (1H, d, J = 2.0 Hz), 7.75ꢀ7.85 (5H, m), 7.40ꢀ7.46 (2H, m), 7.33ꢀ7.38
(4H, m), 6.93 (1H, dd, J = 0.8, 4.0 Hz), 6.86 (1H, dd, J = 2.8, 4.0 Hz), 3.17 (3H, d, J = 2.0 Hz). 13C NMR (101 MHz, CDCl3) δ 144.4 (C,
d, J = 7 Hz), 144.0 (CH), 139.9 (C, d, J = 8 Hz), 135.7 (2C, d, J = 109 Hz), 132.3 (C, d, J = 5 Hz), 131.8 (2x2CH, d, J = 10 Hz), 130.9
(2CH, d, J = 3 Hz), 128.1 (C, d, J = 6 Hz), 127.8 (2x2CH, d, J = 13 Hz), 123.3 (CH), 117.2 (C), 116.0 (C, d, J = 108 Hz), 114.9 (CH),
113.7 (CH), 107.3 (CH), 16.2 (CH3, d, J = 4 Hz). 31P NMR (CDCl3, 162 MHz) δ 33.54 (s). IR (neat, cmꢀ1) 3148 (w), 2968 (w), 1581 (w),
1468 (m), 1434 (m), 1409 (m), 1159 (m), 1100 (m), 873 (m), 730 (s), 722 (s), 696 (s), 537 (s), 518 (s). LCꢀMS (ESI) m/z = 460.9 (M+H).
HRꢀMS (TOFꢀES+) calculated for C24H19N2OPBr 461.0418, found 461.0407 (ꢁ = ꢀ2.4 ppm). Single crystal Xꢀray data: CCDC 1411501;
P21/n; a = 11.8026(2) Ȧ, b = 11.7519(2) Ȧ, c = 17.7173(3) Ȧ; α = 90°, β = 98.8047(17)°, γ = 90°.
Diethyl (7-chloro-4-methylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1f): 1.3 g (73%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.77 (1H, d, J = 2.4 Hz), 7.89 (1H, dd, J = 1.2, 2.4 Hz), 7.79 (1H, dd, J = 1.6, 8.8 Hz), 7.43 (1H, dd, J =
2.4, 8.8 Hz), 6.86 (1H, dd, J = 0.8, 3.6 Hz), 6.85 (1H, dd, J = 2.8, 4.0 Hz), 4.23 (2H, ddq, J = 7.1, 7.9, 10.1 Hz), 4.08 (2H, ddq, J = 7.1, 7.9,
10.1 Hz), 2.91 (3H, d, J = 2.4 Hz), 1.33 (6H, t, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3) δ 140.5 (C, d, J = 11 Hz), 131.2 (C, d, J = 19
Hz), 130.4 (C, d, J = 12 Hz), 129.3 (C), 128.2 (CH), 127.3 (CH), 124.5 (C, d, J = 13 Hz), 115.3 (CH), 114.6 (CH), 113.9 (CH), 110.7 (C,
d, J = 187 Hz), 106.8 (CH), 61.8 (2CH2, d, J = 5 Hz), 17.8 (CH3, d, J = 4 Hz), 16.3 (2CH3, d, J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ
18.55 (s). IR (neat, cmꢀ1)cmꢀ1 2981 (w), 1480 (m), 1408 (m), 1226 (s), 1014 (s), 946 (s), 799 (s), 739 (m), 701 (m), 593 (s), 542 (s). LCꢀ
MS (ESI) m/z = 352.2 (M+H). HRꢀMS (TOFꢀES+) calculated for C17H20NO3PCl 352.0869, found 352.0862 (ꢁ = ꢀ2.0 ppm).
Diethyl (7,9-difluoro-4-methylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1g): 1.4 g (79%, 5 mmol scale).
1H NMR (600 MHz, CDCl3) δ 8.40 (1H, dt, J = 11.8, 2.2 Hz), 8.31 – 8.26 (1H, m), 7.03 (1H, ddd, J = 13.3, 7.7, 2.8 Hz), 6.92 (1H, d, J =
3.9 Hz), 6.83 (1H, dd, J = 4.1, 2.9 Hz), 4.20 (2H, ddq, J = 10.2, 8.4, 7.1 Hz), 4.08 (2H, ddq, J = 10.2, 8.4, 7.1 Hz), 2.91 (3H, d, J = 2.4 Hz),
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1.32 (6H, t, J = 7.1 Hz). 13C NMR (150 MHz, CDCl3) δ 157.3 (CF, dd, J = 242, 13 Hz), 152.5 (CF, ddd, J = 249, 13, 3 Hz), 141.5 (C, d, J
= 11 Hz), 131.4 (C, d, J = 19 Hz), 126.8 (C, ddd, J = 14, 11, 3 Hz), 121.0 (CH, d, J = 24 Hz), 118.8 (C, ddd, J = 12, 9, 3 Hz), 113.6 (CH,
dd, J = 5, 1 Hz), 110.4 (CP, d, J = 181 Hz), 109.7 (CH, ddd, J = 26, 4, 2 Hz), 106.6 (CH, d, J = 1 Hz), 102.9 (CH, dd, J = 28, 26 Hz), 61.8
(2CH2, d, J = 5 Hz), 17.9 (CH3, d, J = 4 Hz), 16.3 (2CH3, d, J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 18.4 (s). 19F NMR (CDCl3, 367
MHz) δ ꢀ115.3 (d, J = 8 Hz), ꢀ118.8 (d, J = 8 Hz). IR (neat, v) 2985 (w), 1628 (m), 1595 (m), 1439 (m), 1365 (m), 1245 (s), 1122 (m),
1016 (s), 952 (s), 795 (m), 714 (m), 559 (s). LCꢀMS (ESI) m/z = 354.9 (M+H). HRꢀMS (TOFꢀES+) calculated for C17H19NO3PF2
354.1071, found 354.1065 (ꢁ = ꢀ1.7 ppm).
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Diethyl (8-chloro-7-fluoro-4-methylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1h): 1.4 g (77%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.70 (1H, d, J = 12.4 Hz), 7.91 (1H, dd, J = 1.8, 6.7 Hz), 7.86 (1H, dd, J = 1.5, 2.5 Hz), 6.90 (1H, dd, J =
1.2, 4.0 Hz), 6.88 (1H, dd, J = 2.8, 4.0 Hz), 4.24 (2H, ddq, J = 7.2, 8.0, 10.1 Hz), 4.10 (2H, ddq, J = 7.2, 8.2, 10.2 Hz), 2.91 (3H, d, J = 2.4
Hz), 1.35 (6H, t, J = 7.2 Hz). 13C NMR (101 MHz, CDCl3) δ 154.2 (CF, d, J = 241 Hz), 140.5 (C, d, J = 11 Hz), 131.2 (C, d, J = 19 Hz),
128.8 (C, dd, J = 2, 12 Hz), 123.2 (C, dd, J = 8, 14 Hz), 120.2 (C, d, J = 20 Hz), 115.7 (CH), 115.6 (CH, m), 114.8 (CH), 114.1 (CH),
110.5 (CP, d, J = 210 Hz), 107.1 (CH), 61.9 (2CH2, d, J = 5 Hz), 17.7 (CH3, d, J = 4 Hz), 16.3 (2CH3, d, J = 6 Hz). 31P NMR (CDCl3, 162
MHz) δ 18.27 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ120.4 (s). IR (neat, cmꢀ1) 2985 (w), 1487 (m), 1410 (m), 1256 (s), 1222 (s), 1015 (s),
960 (s), 728 (s), 700 (s), 626 (m), 556 (s). LCꢀMS (ESI) m/z = 369.9 (M+H). HRꢀMS (TOFꢀES+) calculated for C17H19NO3PFCl
370.0775, found 370.0765 (ꢁ = ꢀ2.7 ppm).
Diethyl (7-chloro-4-methyl-9-nitropyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1i): 1.4 g (70%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 9.13 (1H, d, J = 2.4 Hz), 7.64 (1H, d, J = 2.4 Hz), 7.39 (1H, dd, J = 0.4, 2.8 Hz), 6.99 (1H, d, J = 4.0 Hz),
6.87 (1H, dd, J = 2.8, 4.0 Hz), 4.25 (2H, ddq, J = 10.1, 8.0, 7.1 Hz), 4.11 (2H, ddq, J = 10.1, 8.0, 7.1 Hz), 2.92 (3H, d, J = 1.6 Hz), 1.34
(6H, t, J = 7.1 Hz). 13C NMR (101 MHz, CDCl3) δ 142.1 (C, d, J = 11 Hz), 140.8 (C), 132.2 (C, d, J = 9 Hz), 131.3 (CH, d, J = 2 Hz),
128.3 (C), 127.5 (C, d, J = 16 Hz), 122.4 (CH), 121.7 (C, d, J = 13 Hz), 119.2 (CH), 115.3 (CH), 110.5 (CP, d, J = 190 Hz), 108.2 (CH),
62.2 (2CH2, d, J = 5 Hz), 18.1 (CH3, d, J = 4 Hz), 16.3 (2CH3, d, J = 6 Hz). 31P NMR (CDCl3, 162 MHz) δ 17.25 (s). IR (neat, cmꢀ1)
2980 (w), 1533 (s), 1466 (m), 1408 (m), 1365 (m), 1258 (s), 1230 (s), 1006 (s), 959 (s), 790 (s), 698 (m), 557 (s), 537 (s). LCꢀMS (ESI)
m/z = 397.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C17H19N2O5PCl 397.0720, found 397.0725 (ꢁ = 1.3 ppm).
Diethyl (2-bromo-6-methylpyrrolo[1,2-a][1,5]naphthyridin-5-yl)phosphonate, (1j): 1.4 g (71%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.73 (1H, d, J = 2.0 Hz), 8.26 (1H, app t, J = 2.0 Hz), 7.85 (1H, dd, J = 1.6, 2.4 Hz), 6.90 (1H, dd, J = 1.2,
4.0 Hz), 6.88 (1H, dd, J = 2.8, 4.0 Hz), 4.27 (2H, m), 4.19 (2H, m), 2.95 (3H, d, J = 2.8 Hz), 1.32 (6H, t, J = 7.2 Hz). 13C NMR (101 MHz,
CDCl3) δ 145.8 (CH), 142.9 (C, d, J = 11 Hz), 140.3 (C, d, J = 8 Hz), 131.5 (C, d, J = 19 Hz), 128.3 (C, d, J = 10 Hz), 123.5 (CH), 117.5
(C), 115.8 (CH), 115.2 (CH), 114.8 (C, d, J = 190 Hz), 107.7 (CH), 62.1 (2CH2, d, J = 6 Hz), 17.7 (CH3, d, J = 4 Hz), 16.4 (2CH3, d, J = 7
Hz). 31P NMR (CDCl3, 162 MHz) δ 17.49 (s). IR (neat, cmꢀ1) 2979 (w), 1584 (w), 1471 (m), 1305 (m), 1224 (m), 1102 (m), 1021 (s), 960
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(s), 717 (s), 602 (s), 555 (s). LCꢀMS (ESI) m/z = 396.9 (M+H). HRꢀMS (TOFꢀES+) calculated for C16H19N2O3PBr 397.0317, found
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Diethyl (1-(3,5-difluoro-2-(1H-pyrrol-1-yl)phenyl)-3-methylbuta-1,2-dien-1-yl)phosphonate, (2f): 1.8 g (83%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.21 (1H, ddt, J = 8.9, 3.0, 1.6 Hz), 6.90 – 6.82 (1H, m), 6.75 (2H, td, J = 2.1, 1.1 Hz), 6.25 (2H, t, J = 2.1
Hz), 4.14 – 3.96 (4H, m), 1.48 (6H, d, J = 6.7 Hz), 1.28 (6H, td, J = 7.1, 0.7 Hz). 13C NMR (101 MHz, CDCl3) δ 208.0 (C, d, J = 3 Hz),
161.0 (CF, ddd, J = 251, 13, 2 Hz), 158.3 (CF, dd, J = 252, 13 Hz), 134.5 (C, t, J = 10.1 Hz), 124.9 (C, ddd, J = 12, 8, 4 Hz), 123.0 (2CH),
112.9 (CH, dt, J = 23, 3 Hz), 109.1 (2CH), 103.8 (CH, ddd, J = 26, 25, 2 Hz), 99.0 (C, d, J = 15 Hz), 89.3 (CP, d, J = 199 Hz), 62.8 (2CH2,
d, J = 7 Hz), 19.1 (2CH3, d, J = 7 Hz), 16.3 (2CH3, d, J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 14.63 (s). 19F NMR (CDCl3, 367 MHz) δ
ꢀ109.7 (d, J = 8 Hz), ꢀ117.5 (d, J = 8 Hz). IR (neat, cmꢀ1) 2989 (w), 1963 (w), 1597 (m), 1509 (s), 1440 (m), 1299 (m), 1234 (s), 1140 (m),
1015 (s), 973 (s), 955 (s), 735 (s), 611 (s), 600 (s), 565 (s). LCꢀMS (ESI) m/z = 382.0 (M+H). HRꢀMS (TOFꢀES+) calculated for
C19H23NO3PF2 382.1384, found 382.1376 (ꢁ = ꢀ2.1 ppm). Melting point: 90 °C (decomposition). Single crystal Xꢀray data: CCDC
1411502; P21/n; a = 8.01820(10) Ȧ, b = 14.4498(2) Ȧ, c = 16.8318(2) Ȧ; α = 90°, β = 100.2909(17)°, γ = 90°.
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(1-(3,5-Difluoro-2-(1H-pyrrol-1-yl)phenyl)-3-methylbuta-1,2-dien-1-yl)diphenylphosphine oxide, (2f’): 2.0 g (90%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.71 – 7.62 (4H, m), 7.54 – 7.47 (2H, m), 7.47 – 7.39 (4H, m), 7.09 (1H, ddt, J = 9.1, 3.0, 1.5 Hz), 6.79
(1H, dddd, J = 9.1, 8.1, 2.9, 0.8 Hz), 6.73 (2H, td, J = 2.1, 0.7 Hz), 6.28 (2H, t, J = 2.1 Hz), 1.18 (6H, d, J = 6.1 Hz). 13C NMR (101 MHz,
CDCl3) δ 209.6 (C, d, J = 5 Hz), 161.1 (CF, ddd, J = 251, 13, 2 Hz), 158.8 (CF, dd, J = 252, 13 Hz), 134.8 – 134.5 (C, m), 131.9 (2CH, d,
J = 3 Hz), 131.9 (2CP, d, J = 106 Hz), 131.7 (2x2CH, d, J = 10 Hz), 128.3 (2x2CH, d, J = 12 Hz), 125.1 (C, m), 123.3 (2CH), 112.8 (CH,
dt, J = 24, 3 Hz), 109.2 (2CH), 103.7 (CH, t, J = 26 Hz), 99.5 (C, d, J = 13 Hz), 93.3 (CP, d, J = 103 Hz), 18.9 (2CH3, d, J = 6 Hz). 31P
NMR (CDCl3, 162 MHz) δ 30.59 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ108.8 (d, J = 8 Hz), ꢀ117.3 (d, J = 8 Hz). IR (neat, cmꢀ1) 3019 (w),
1956 (w), 1592 (w), 1510 (m), 1437 (m), 1294 (m), 1184 (s), 1140 (m), 893 (m), 739 (s), 696 (s), 593 (s), 535 (s), 520 (s). LCꢀMS (ESI)
m/z = 446.1 (M+H). HRꢀMS (TOFꢀES+) calculated for C27H23NOPF2 446.1485, found 446.1482 (ꢁ = ꢀ0.7 ppm). Melting point: 145 °C
(decomposition).
Diethyl (7,9-difluoro-4-isopropylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1k): 1.6 g ( 83%, 5 mmol scale).
1H NMR (700 MHz, CDCl3) δ 8.63 (1H, td, J = 2.8, 11.9 Hz), 8.29 (1H, dt, J = 2.7, 1.1 Hz), 7.12 (1H, dt, J = 4.1, 1.2 Hz), 7.03 (1H, ddd,
J = 13.3, 7.6, 2.8 Hz), 6.85 (1H, dd, J = 4.1, 2.9 Hz), 4.60 (1H, dsept, J = 7.1, 0.6 Hz), 4.22 (2H, ddq, J = 10.2, 8.0, 7.1 Hz), 4.10 (2H, ddq,
J = 10.2, 8.0, 7.1 Hz), 1.55 (6H, d, J = 7.1 Hz), 1.33 6H, (td, J = 7.1, 0.6 Hz). 13C NMR (175 MHz, CDCl3) δ 157.2 (CF, dd, J = 13, 242
Hz), 152.4 (CF, ddd, J = 3, 13, 247 Hz), 151.8 (C, d, J = 12 Hz), 128.2 (C, d, J = 18 Hz), 127.2 (C, ddd, J = 16, 11, 3 Hz), 119.8 (CH, d, J
= 25 Hz), 119.2 – 118.4 (C, m), 113.2 (CH, dd, J = 5, 1 Hz), 110.3 (CP, td, J = 3, 190 Hz), 110.2 (CH, ddd, J = 26, 4, 2 Hz), 108.9 (CH, d,
J = 1 Hz), 103.0 (CH, dd, J = 28, 26 Hz), 62.0 (2CH2, d, J = 5 Hz), 31.4 (CH, d, J = 5 Hz), 21.8 (2CH3), 16.3 (2CH3, d, J = 7 Hz). 31P
NMR (CDCl3, 283 MHz) δ 18.90 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.4 (d, J = 7 Hz), ꢀ118.6 (m). IR (neat, cmꢀ1) 2981 (w), 1628
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(w), 1595 (m), 1442 (m), 1339 (m), 1247 (s), 1128 (m), 1044 (s), 1016 (s), 958 (s), 716 (s), 558 (s). LCꢀMS (ESI) m/z = 381.4 (M+H).
HRꢀMS (TOFꢀES+) calculated for C19H23NO3PF2 382.1384, found 382.1379 (ꢁ = ꢀ1.3 ppm).
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(7,9-Difluoro-4-isopropylpyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1l): 0.9 g ( 41%, 5 mmol scale).
1H NMR (700 MHz, CDCl3) δ 8.31 (1H, dt, J = 2.8, 1.2 Hz), 8.14 (1H, dddd, J = 11.7, 2.8, 1.8, 0.8 Hz), 7.75 (4H, ddd, J = 12.3, 8.3, 1.3
Hz), 7.57 – 7.51 (2H, m), 7.50 – 7.44 (4H, m), 6.98 – 6.94 (2H, m,), 6.84 (1H, dd, J = 4.1, 2.9 Hz), 3.62 (1H, dsept, J = 7.0, 1.4 Hz), 1.07
(6H, d, J = 7.0 Hz). 13C NMR (175 MHz, CDCl3) δ 156.7 (CF, dd, J = 243, 13 Hz), 152.4 (CF, ddd, J = 249, 13, 2 Hz), 150.2 (C, d, J = 9
Hz), 135.1 (2CP, d, J = 105 Hz), 131.8 (2CH, d, J = 3 Hz), 131.6 (2x2CH, d, J = 10 Hz), 128.8 (2x2CH, d, J = 13 Hz), 128.3 (C, d, J = 12
Hz), 127.9 (C, td, J = 11, 3 Hz), 120.0 (CH, d, J = 24 Hz), 119.2 – 118.7 (C, m), 113.2 (CH, d, J = 4 Hz), 113.1 (CP, d, J = 107 Hz), 110.8
(CH, dt, J = 26, 4 Hz), 108.4 (CH, d, J = 1 Hz), 103.0 (CH, dd, J = 28, 26 Hz), 33.4 (CH, d, J = 8 Hz), 21.0 (2CH3). 31P NMR (CDCl3,
283 MHz) δ 32.06 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.4 (d, J = 7 Hz), ꢀ118.6 (m). IR (neat, cmꢀ1) 2959 (w), 1597 (m), 1473 (m),
1436 (s), 1179 (s), 1115 (m), 998 (m), 769 (m), 720 (s), 690 (s), 592 (m), 527 (s). LCꢀMS (ESI) m/z = 445.4 (M+H). HRꢀMS (TOFꢀES+)
calculated for C27H23NOPF2 446.1485, found 446.1492 (ꢁ = 1.6 ppm).
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(7,9-Difluoro-4-(propan-2-ylidene)-4,5-dihydropyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1l’): 0.8 g (37%, 5 mmol scale).
1H NMR (700 MHz, CDCl3) δ 7.89–7.83 (2H, m), 7.58–7.52 (1H, m), 7.49 – 7.44 (2H, m), 7.31 (1H, tt, J = 7.0, 1.6 Hz), 7.22 – 7.14 (4H,
m), 7.01 (1H, dq, J = 8.4, 2.0 Hz), 6.85 (1H, dq, J = 4.0, 1.4 Hz), 6.79 (1H, ddt, J = 13.0, 8.3, 2.4 Hz), 6.30 (1H, dd, J = 3.8, 1.4 Hz), 6.23
(1H, t, J = 3.3 Hz), 4.75 (1H, d, J = 20.2 Hz), 1.97 (3H, d, J = 5.7 Hz), 1.41 (3H, d, J = 3.7 Hz). 13C NMR (175 MHz, CDCl3) δ 157.9
(CF, ddd, J = 247, 12, 4 Hz), 151.9 (CF, ddd, J = 250, 12, 4 Hz), 132.9 (C, d, J = 11 Hz), 132.2 (2CH, d, J = 8 Hz), 132.0 (CH, d, J = 3
Hz), 131.2 (CH, d, J = 3 Hz), 130.7 (2CH, d, J = 9 Hz), 129.8 (CP, d, J = 161 Hz), 129.2 (CP, d, J = 159 Hz), 128.3 (C, d, J = 2 Hz), 127.9
(2CH, d, J = 11 Hz), 127.8 (2CH, d, J = 12 Hz), 127.6 (C, ddd, J = 9, 6, 3 Hz), 121.6 (C, dt, J = 9, 4 Hz), 119.4 (CH, d, J = 15 Hz), 115.2
(C, d, J = 7 Hz), 112.8 (CH, dt, J = 23, 4 Hz), 110.4 (CH, d, J = 3 Hz), 110.0 (CH), 104.3 (CH, ddd, J = 26, 25, 3 Hz), 49.9 (CH, d, J = 58
Hz), 23.4 (CH3, d, J = 3 Hz), 21.0 (CH3, d, J = 3 Hz). 31P NMR (CDCl3, 283 MHz) δ 27.48 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.4
(m), ꢀ122.5 (m). IR (neat, cmꢀ1) 2956 (w), 1625 (w), 1507 (s), 1437 (s), 1302 (m), 1185 (s), 1125 (s), 831 (m), 716 (s), 695 (s), 519 (s).
LCꢀMS (ESI) m/z = 446.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C27H23NOPF2 446.1485, found 446.1483 (ꢁ = ꢀ0.4 ppm).
Diethyl (1-(5-cyano-2-(1H-pyrrol-1-yl)phenyl)3-methylbuta-1,2-dien-1-yl)phosphonate, (2g): 1.7 g (90%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.90 (1H, t, J = 1.7 Hz), 7.58 (1H, ddd, J = 8.2, 1.9, 1.0 Hz), 7.31 (1H, d, J = 8.0 Hz), 6.93 (2H, t, J = 2.2
Hz), 6.28 – 6.22 (2H, t, J = 2.2 Hz), 4.16 – 4.00 (4H, m), 1.44 (6H, d, J = 6.7 Hz), 1.28 (6H, td, J = 7.1, 0.7 Hz). 13C NMR (101 MHz,
CDCl3) δ 208.1 (C, d, J = 4 Hz), 143.8 (C, d, J = 7 Hz), 135.0 (CH, d, J = 2 Hz), 132.0 (CH, d, J = 1 Hz), 130.5 (C, d, J = 10 Hz), 127.4
(CH), 122.0 (2CH), 118.1 (CN), 110.5 (C, d, J = 2 Hz), 110.3 (2CH), 99.2 (C, d, J = 16 Hz), 89.6 (CP, d, J = 201 Hz), 62.9 (2CH, d, J = 7
Hz), 18.6 (2CH3, d, J = 7 Hz), 16.3 (2CH3, d, J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 14.47 (s). IR (neat, cmꢀ1) 2978 (w), 2230 (m),
1955 (w), 1601 (w), 1504 (s), 1333 (m), 1238 (s), 1113 (m), 1049 (m), 1018 (s), 964 (s), 724 (s), 571 (m). LCꢀMS (ESI) m/z = 371.0
(M+H). HRꢀMS (TOFꢀES+) calculated for C20H24N2O3P 371.1525, found 371.1517 (ꢁ = ꢀ2.2 ppm).
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3-(1-(Diphenylphosphoryl)-3-methylbuta-1,2-dien-1-yl)-4-(1H-pyrrol-1-yl)benzonitrile, (2g’): 1.9 g (88%, 5 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 7.74 – 7.64 (4H, m), 7.59 – 7.52 (4H, m), 7.50 – 7.43 (4H, m), 7.32 (1H, d, J = 8.0 Hz), 6.96 – 6.89 (2H, t,
J = 2.1 Hz), 6.29 (2H, t, J = 2.1 Hz,), 1.22 (6H, d, J = 6.0 Hz,). 13C NMR (101 MHz, CDCl3) δ 209.3 (C, d, J = 6 Hz), 144.5 (C, d, J = 5
Hz), 134.6 (CH, d, J = 2 Hz), 132.1 (2CH, d, J = 3 Hz), 132.0 (CH), 131.8 (2CP, d, J = 106 Hz), 131.7 (2x2CH, d, J = 10 Hz), 131.2 (C, d,
J = 8 Hz), 128.4 (2x2CH, d, J = 12 Hz), 128.1 (CH), 122.5 (2CH), 118.0 (CN), 111.0 (C), 110.0 (2CH), 99.4 (C, d, J = 13 Hz), 93.6 (CP,
d, J = 103 Hz), 18.6 (2CH3, d, J = 5 Hz). 31P NMR (CDCl3, 162 MHz) δ 29.71 (s). IR (neat, cmꢀ1) 3058 (w), 2230 (m), 1956 (w), 1500
(m), 1436 (m), 1329 (m), 1182 (m), 1117 (m), 1100 (m), 916 (m), 723 (s), 693 (s), 546 (s), 533 (s). LCꢀMS (ESI) m/z = 435.1 (M+H).
HRꢀMS (TOFꢀES+) calculated for C28H24N2OP 435.1626, found 435.1622 (ꢁ = ꢀ0.9 ppm).
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Diethyl (7-cyano-4-isopropylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1m): 1.4 g (78%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 9.38 (1H, d, J = 1.7 Hz), 7.93 – 7.86 (2H, m), 7.70 (1H, dd, J = 8.6, 1.8 Hz), 7.11 (1H, d, J = 3.6 Hz), 6.91
(1H, dd, J = 4.1, 2.9 Hz), 4.64 (1H, pd, J = 7.1, 1.0 Hz), 4.25 (2H, ddq, J = 10.1, 7.9, 7.1 Hz), 4.12 (2H, ddq, J = 10.1, 8.0, 7.1 Hz), 1.54
(6H, d, J = 7.1 Hz), 1.34 (6H, td, J = 7.0, 0.6 Hz). 13C NMR (101 MHz, CDCl3) δ 151.4 (C, d, J = 12 Hz), 134.4 (CH), 134.2 (C, d, J = 13
Hz), 129.9 (CH), 128.2 (C, d, J = 18 Hz), 123.8 (C, d, J = 15 Hz), 119.2 (CN), 115.0 (CH, d, J = 1 Hz), 114.6 (CH, d, J = 1 Hz), 114.2
(CH), 110.7 (CP, d, J = 190 Hz), 110.2 (CH), 107.2 (C), 62.2 (2CH2, d, J = 5 Hz), 31.3 (CH, d, J = 5 Hz), 21.7 (2CH3), 16.3 (2CH3, d, J =
7 Hz). 31P NMR (CDCl3, 162 MHz) δ 18.38 (s). IR (neat, cmꢀ1) 2933 (w), 2224 (m), 1606 (m), 1512 (s), 1436 (s), 1346 (s), 1179 (s),
1119 (m), 822 (m), 700 (s), 596 (m), 524 (s), 504 (s). LCꢀMS (ESI) m/z = 371.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C20H24N2O3P
371.1525, found 371.1516 (ꢁ = ꢀ2.4 ppm).
5-(Diphenylphosphoryl)-4-isopropylpyrrolo[1,2-a]quinoline-7-carbonitrile, (1n): 0.8 g (38%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.92 (1H, d, J = 1.7 Hz), 7.96 (1H, dd, J = 3.1, 1.2 Hz), 7.91 (1H, dd, J = 8.7, 1.5 Hz), 7.78 – 7.71 (4H, m),
7.62 (1H, dd, J = 8.7, 1.8 Hz), 7.59 – 7.54 (2H, m), 7.52 – 7.46 (4H, m), 6.95 (1H, dd, J = 4.1, 1.2 Hz), 6.90 (1H, dd, J = 4.0, 2.9 Hz), 3.62
(1H, pd, J = 7.0, 1.5 Hz), 1.07 (6H, d, J = 6.9 Hz). 13C NMR (101 MHz, CDCl3) δ 149.7 (C, d, J = 9 Hz), 134.9 (2CP, d, J = 105 Hz),
134.5 (CH, d, J = 4 Hz), 134.4 (C, d, J = 9 Hz), 132.1 (2CH, d, J = 3 Hz), 131.6 (2x2CH, d, J = 10 Hz), 129.9 (CH), 128.9 (2x2CH,d, J =
12 Hz), 128.3 (C, d, J = 12 Hz), 124.6 (C, d, J = 11 Hz), 118.7 (CN), 115.2 (CH), 114.6 (CH), 114.4 (CH), 113.7 (CP, d, J = 105 Hz),
109.7 (CH), 106.7 (C), 33.4 (CH, d, J = 8 Hz), 20.8 (2CH3). 31P NMR (CDCl3, 162 MHz) δ 31.96 (s). IR (neat, cmꢀ1) 2935 (w), 2227 (m),
1604 (w), 1482 (m), 1438 (m), 1166 (m), 1116 (m), 1099 (m), 908 (m), 725 (s), 691 (s), 524 (s). LCꢀMS (ESI) m/z = 434.7 (M+H). HRꢀ
MS (TOFꢀES+) calculated for C28H24N2OP 435.1626, found 435.1619 (ꢁ = ꢀ1.6 ppm).
5-(Diphenylphosphoryl)-4-(propan-2-ylidene)-4,5dihydropyrrolo[1,2-a]quinoline-7-carbonitrile, (1n’): 0.7 g (32%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.88 – 7.80 (2H, m), 7.63 (1H, t, J = 2.2 Hz), 7.60 – 7.53 (1H, m), 7.52 – 7.44 (3H, m), 7.35 – 7.29 (1H,
m), 7.25 – 7.21 (2H, m), 7.20 – 7.13 (2H, m), 7.08 (1H, d, J = 8.4 Hz), 6.64 (1H, dd, J = 3.1, 1.4 Hz), 6.34 (1H, dd, J = 3.7, 1.4 Hz), 6.31
(1H, t, J = 3.3 Hz), 4.76 (1H, d, J = 19.4 Hz), 1.97 (3H, d, J = 5.7 Hz), 1.44 (3H, d, J = 3.8 Hz). 13C NMR (101 MHz, CDCl3) δ 139.5 (C,
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d, J = 4 Hz), 134.0 (C, d, J = 11 Hz), 133.8 (CH, d, J = 5 Hz), 132.4 (CH, d, J = 3 Hz), 132.2 (2CH, d, J = 7.9 Hz), 132.1 (CH), 131.4 (CH,
d, J = 3 Hz), 130.8 (2CH, d, J = 9 Hz), 130.0 (CP, d, J = 95 Hz), 128.9 (CP, d, J = 95 Hz), 128.9 (C, d, J = 2 Hz), 128.1 (2CH, d, J = 11
Hz), 127.9 (2CH, d, J = 12 Hz), 124.3 (C, d, J = 7 Hz), 118.5 (CN), 115.7 (CH, d, J = 3 Hz), 115.3 (CH), 114.7 (C, d, J = 7 Hz), 112.3
(CH), 111.6 (CH), 107.1 (C, d, J = 3 Hz), 48.6 (CH, d, J = 58 Hz), 23.6 (CH3), 21.3 (CH3). 31P NMR (CDCl3, 162 MHz) δ 27.45 (s). IR
(neat, cmꢀ1) 2977 (w), 2224 (m), 1602 (w), 1428 (m), 1354 (m), 1229 (m), 1164 (m), 1014 (s), 935 (s), 818 (s), 714 (s), 612 (s), 547 (s).
LCꢀMS (ESI) m/z = 435.1 (M+H). HRꢀMS (TOFꢀES+) calculated for C28H24N2OP 435.1626, found 435.1611 (ꢁ = ꢀ3.4 ppm).
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Diethyl (1-(5-bromo-2-(1H-pyrrol-1-yl)phenyl)-3-methylbuta-1,2-dien-1-yl)phosphonate, (2h): 1.9 g (90%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.79 – 7.73 (1H, m), 7.45 (1H, ddd, J = 8.4, 2.3, 1.2 Hz), 7.12 (1H, dd, J = 8.4, 0.9 Hz), 6.89 (2H, t, J = 2.2
Hz), 6.24 (2H, t, J = 2.2 Hz), 4.19 – 4.00 (4H, m,), 1.47 (6H, d, J = 6.7 Hz), 1.30 (6H, t, J = 7.1 Hz). 13C NMR (101 MHz, CDCl3) δ 208.1
(C, d, J = 4 Hz), 139.3 (C, d, J = 7 Hz), 133.6 (CH, d, J = 3 Hz), 131.5 (C), 131.4 (CH, d, J = 2 Hz), 128.5 (CH), 122.3 (2CH), 120.5 (C, d,
J = 2 Hz), 109.3 (2CH), 98.5 (C, d, J = 16 Hz), 89.7 (CP, d, J = 199 Hz), 62.8 (2CH2, d, J = 7 Hz), 18.8 (2CH3, d, J = 7 Hz), 16.3 (2CH3, d,
J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 14.92 (s). IR (neat, cmꢀ1) 3109 (w), 2978 (w), 1965 (w), 1499 (s), 1327 (m), 1238 (s), 1113
(m), 1013 (s), 966 (s), 831 (m), 721 (s), 582 (s), 565 (s). LCꢀMS (ESI) m/z = 423.9 (M+H). HRꢀMS (TOFꢀES+) calculated for
C19H24NO3PBr 424.0677, found 424.0684 (ꢁ = 1.7 ppm). Melting point: 95 °C (decomposition).
(1-(5-Bromo-2-(1H-pyrrol-1-yl)phenyl)-3-methylbuta-1,2-dien-1-yl)diphenylphosphine oxide, (2h’): 2.1 g (87%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.72 – 7.64 (4H, m), 7.56 – 7.49 (2H, m), 7.45 (5H, m), 7.39 (1H, ddd, J = 8.4, 2.3, 0.9 Hz), 7.09 (1H, dd,
J = 8.4, 0.7 Hz), 6.83 (2H, t, J = 2.1 Hz), 6.24 (2H, t, J = 2.1 Hz), 1.21 (6H, d, J = 6.0 Hz). 13C NMR (101 MHz, CDCl3) δ 209.3 (C, d, J
= 6 Hz), 139.8 (C, d, J = 5 Hz), 133.4 (CH, d, J = 3 Hz), 132.1 (2CP, d, J = 106 Hz), 131.9 (C), 131.8 (2CH, m), 131.7 (2x2CH, d, J = 10
Hz), 131.3 (CH, d, J = 1 Hz), 129.1 (CH), 128.3 (2x2CH, d, J = 12 Hz), 122.8 (2CH), 120.9 (C, d, J = 2 Hz), 109.1 (2CH), 99 (C, d, J = 13
Hz), 93.9 (CP, d, J = 103 Hz), 18.7 (2CH3, d, J = 6 Hz). 31P NMR (CDCl3, 162 MHz) δ 29.78 (s). IR (neat, cmꢀ1) 3059 (w), 1955 (w),
1589 (m), 1437 (m), 1181 (s), 1117 (m), 1068 (m), 913 (m), 722 (s), 693 (s), 558 (s). LCꢀMS (ESI) m/z = 487.9 (M+H). HRꢀMS (TOFꢀ
ES+) calculated for C27H24NOPBr 488.0779, found 488.0767 (ꢁ = ꢀ2.5 ppm). Melting point: 145 °C (decomposition).
Diethyl (7-bromo-4-isopropylpyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1o): 1.7 g (79%, 5 mmol scale).
1H NMR (700 MHz, CDCl3) δ 9.14 (1H, d, J = 2.1 Hz), 7.87 (1H, dd, J = 3.0, 1.3 Hz), 7.72 (1H, dd, J = 8.8, 2.0 Hz), 7.55 (1H, dd, J =
8.8, 2.2 Hz), 7.05 (1H, m), 6.85 (1H, dd, J = 4.0, 2.8 Hz), 4.64 (1H, sept., J = 7.1 Hz), 4.24 (2H, ddq, J = 10.1, 7.9, 7.1 Hz), 4.10 (2H, ddq,
J = 10.1, 7.9, 7.1 Hz), 1.53 (6H, d, J = 7.1 Hz), 1.34 (6H, t, J = 7.1 Hz). 13C NMR (175 MHz, CDCl3) δ 150.7 (C, d, J = 12 Hz), 131.7
(CH, d, J = 2 Hz), 130.7 (C, d, J = 13 Hz), 130.1 (CH), 127.9 (C, d, J = 18 Hz), 125.1 (C, d, J = 15 Hz), 116.9 (C), 115.5 (CH), 113.5
(2CH, m), 110.4 (C, d, J = 188 Hz), 109.3 (CH), 61.9 (2CH2, d, J = 5 Hz), 31.2 (CH, d, J = 5 Hz), 21.7 (2CH3, d, J = 1 Hz), 16.3 (2CH3, d,
J = 7 Hz). 31P NMR (CDCl3, 162 MHz) δ 19.01 (s). IR (neat, cmꢀ1) 2979 (w), 1475 (m), 1426 (m), 1224 (m), 1042 (s), 1015 (s), 957 (s),
804 (s), 730 (s), 550 (s). LCꢀMS (ESI) m/z = 424.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C19H24NO3PBr 424.0677, found 424.0671
(ꢁ = ꢀ1.4 ppm).
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7-Bromo-4-isopropylpyrrolo[1,2-a]quinolin-5-yldiphenylphosphine oxide, (1p): 0.9 g (36%, 5 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 8.48 (1H, dd, J = 2.1, 0.7 Hz), 7.90 (1H, dd, J = 2.9, 1.3 Hz), 7.81 – 7.68 (5H, m), 7.53 (2H, ddt, J = 8.3,
4.7, 1.5 Hz), 7.50 – 7.44 (5H, m), 6.92 (1H, dd, J = 4.1, 1.3 Hz), 6.84 (1H, dd, J = 4.1, 2.9 Hz), 3.77 (1H, dtd, J = 13.9, 6.9, 1.6 Hz), 1.11
(6H, d, J = 6.9 Hz). 13C NMR (101 MHz, CDCl3) δ 149.7 (C, d, J = 9 Hz), 135.4 (2CP, d, J = 105 Hz), 132.0 (CH, d, J = 4 Hz), 131.7
(2CH, d, J = 3 Hz), 131.6 (2x2CH, d, J = 10 Hz), 130.9 (C, d, J = 9.1 Hz), 130.1 (CH), 128.8 (2x2CH, d, J = 12 Hz), 128.1 (C, d, J = 12
Hz), 125.7 (C, d, J = 11 Hz), 116.2 (C), 115.7 (CH), 113.7 (CH), 113.6 (CH), 113.4 (CP, d, J = 107 Hz), 108.8 (CH), 33.2 (CH, d, J = 8
Hz), 21.0 (2CH3). 31P NMR (CDCl3, 162 MHz) δ 31.23 (s). IR (neat, cmꢀ1) 2968 (w), 1476 (w), 1437 (w), 1326 (m), 1171 (m), 1115 (m),
1099 (m), 906 (m), 747 (s), 722 (s), 691 (s), 519 (s). LCꢀMS (ESI) m/z = 487.9 (M+H). HRꢀMS (TOFꢀES+) calculated for C27H24NOPBr
488.0779, found 488.0782 (ꢁ = 0.6 ppm).
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7-Bromo-4-(propan-2-ylidene)-4,5-dihydropyrrolo[1,2-a]quinolin-5-yl)diphenylphosphine oxide, (1p’): 1.0 g (40 %, 5 mmol scale).
1H NMR (700 MHz, CDCl3) δ 7.87 – 7.80 (2H, m), 7.54 (1H, td, J = 7.4, 1.4 Hz), 7.52 (1H, t, J = 2.4 Hz), 7.47 – 7.43 (2H, m), 7.33 (1H,
dt, J = 8.5, 2.2 Hz), 7.30 (1H, tt, J = 7.3, 1.4 Hz), 7.23 (2H, ddd, J = 11.2, 8.1, 1.4 Hz), 7.17 – 7.12 (2H, m), 6.89 (1H, d, J = 8.5 Hz), 6.55
(1H, dd, J = 3.0, 1.4 Hz), 6.28 (1H, dd, J = 3.6, 1.4 Hz), 6.22 (1H, t, J = 3.3 Hz), 4.72 (1H, d, J = 20.4 Hz), 1.97 (3H, d, J = 5.7 Hz), 1.44
(3H, d, J = 3.7 Hz). 13C NMR (175 MHz, CDCl3) δ 135.3 (C, d, J = 5 Hz), 133.1 (C, d, J = 11 Hz), 132.9 (CH, d, J = 4 Hz), 132.3 (2CH,
d, J = 8 Hz), 131.8 (CH, d, J = 3 Hz), 131.2 (CH, d, J = 3 Hz), 131.1 (CH, d, J = 3 Hz), 130.8 (2CH, d, J = 9 Hz), 130.2 (CP, d, J = 95 Hz),
129.2 (CP, d, J = 94 Hz), 128.3 (C, d, J = 2 Hz), 127.8 (2CH, d, J = 11 Hz), 127.7 (2CH, d, J = 12 Hz), 125.1 (C, d, J = 6 Hz), 116.6 (C, d,
J = 4 Hz), 116.6 (CH, d, J = 3 Hz), 115.4 (C, d, J = 7 Hz), 114.9 (CH), 111.0 (CH), 110.7 (CH, d, J = 1 Hz), 48.8 (CH, d, J = 58 Hz), 23.5
(CH3, d, J = 3 Hz), 21.2 (CH3, d, J = 3 Hz). 31P NMR (CDCl3, 283 MHz) δ 27.47 (s). IR (neat, cmꢀ1) 2933 (w), 2847 (w), 1499 (s), 1436
(s), 1342 (s), 1179 (s), 1107 (s), 901 (s), 806 (s), 697 (s), 592 (s), 524 (s), 508 (s). LCꢀMS (ESI) m/z = 487.9 (M+H). HRꢀMS (TOFꢀES+)
calculated for C27H24NOPBr 488.0779, found 488.0789 (ꢁ = ꢀ1.6 ppm).
Diethyl (1-(3,5-difluoro-2-(1H-pyrrol-1-yl)phenyl)-3-phenylbuta-1,2-dien-1-yl)phosphonate, (2r): 1.2 g (89%, 3 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.37 – 7.27 (m, 3H), 7.25 – 7.16 (m, 3H), 6.95 – 6.86 (1H, m), 6.80 (2H, td, J = 2.1, 1.1 Hz), 6.29 (2H, t, J
= 2.1 Hz), 4.19 – 3.94 (4H, m), 1.76 (3H, d, J = 6.7 Hz), 1.27 (3H, td, J = 7.2, 0.4 Hz), 1.25 (3H, td, J = 7.2, 0.4 Hz). 13C NMR (101 MHz,
CDCl3) δ 210.7 (C, d, J = 2 Hz), 161.0 (CF, ddd, J = 242, 12, 2 Hz), 158.4 (CF, dd, J = 253, 13 Hz), 134.0 (C, d, J = 8 Hz), 133.6 (C, t, J =
10 Hz), 128.6 (2CH, d, J = 1 Hz), 127.9 (CH, d, J = 2 Hz), 126.1 (2CH, d, J = 2 Hz), 125.0 (C, m), 123.1 (2CH), 112.9 (CH, dt, J = 23, 3
Hz), 109.4 (2CH), 104.2 (CH, t, J = 25 Hz), 104.1 (C, m), 93.8 (C, d, J = 197 Hz), 63.1 (2CH2, t, J = 7 Hz), 16.3 (CH3, d, J = 3 Hz), 16.3
(CH3, d, J = 3 Hz), 15.4 (CH3, d, J = 7 Hz). 31P NMR (CDCl3, 283 MHz) δ 13.99 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ109.3 (d, J = 7.4
Hz), ꢀ117.0 (d, J = 7.4 Hz). IR (neat, cmꢀ1) 2971 (m), 1945 (w), 1739 (s), 1597 (w), 1508 (m), 1438 (m), 1366 (s), 1230 (s), 1218 (s),
1047 (s), 1018 (s), 970 (m), 761 (m), 728 (m). LCꢀMS (ESI) m/z = 444.0 (M+H). HRꢀMS (TOFꢀES+) calculated for C24H25NO3PF2
444.1540, found 444.1527 (ꢁ = ꢀ2.9 ppm).
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Diethyl (4-ethyl-7,9-difluoropyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1q): 0.9 g (50%, 5 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 8.30 (1H, dt, J = 1.7, 0.7 Hz), 8.28 – 8.21 (1H, m), 7.05 (1H, ddd, J = 13.3, 7.7, 2.8 Hz), 6.96 (1H, dd, J =
3.3, 2.0 Hz), 6.86 (1H, dd, J = 4.1, 2.9 Hz), 4.22 (2H, ddq, J = 10.1, 7.9, 7.1 Hz), 4.08 (2H, ddq, J = 10.1, 8.3, 7.1 Hz), 3.51 (2H, qd, J =
7.4, 1.6 Hz), 1.40 (3H, t, J = 7.5 Hz), 1.32 (6H, td, J = 7.1, 0.5 Hz). 13C NMR (175 MHz, CDCl3) δ 157.2 (CF, dd, J = 242, 13 Hz), 152.6
(CF, ddd, J = 249, 13, 3 Hz), 148.2 (C, d, J = 13 Hz), 130.7 (C, d, J = 19 Hz), 127.0 – 126.5 (C, m), 120.8 (CH, d, J = 24 Hz), 118.9 (C, td,
J = 9, 5 Hz), 114.0 – 113.4 (CH, m), 109.9 (CH, dt, J = 26, 3 Hz), 109.4 (CP, d, J = 192 Hz), 106.6 (CH), 102.9 (CH, dd, J = 28, 26 Hz),
61.8 (2CH2, d, J = 5 Hz), 24.6 (CH2, d, J = 4 Hz), 16.3 (2CH3, d, J = 7 Hz), 15.9 (CH3, d, J = 2Hz). 31P NMR (CDCl3, 283 MHz) δ 17.85
(s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.6 (m), ꢀ118.6 (m). IR (neat, cmꢀ1): 2981 (w), 1630 (m), 1596 (s), 1508 (m), 1473 (m), 1441 (s),
1272 (s), 1250 (s), 1129 (m), 1018 (s), 959 (s), 786 (m), 720 (m), 559 (m). LCꢀMS (ESI) m/z = 368.5 (M+H). HRꢀMS (TOFꢀES+) calcuꢀ
lated for C18H21NO3PF2 368.1227, found 368.1230 (ꢁ = 0.8 ppm).
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(Z)-Diethyl (4-ethylidene-7,9-difluoro-4,5-dihydropyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1q’): 0.6 g (35%, 5 mmol scale).
1H NMR (400 MHz, CDCl3) δ 7.44 (1H, td, J = 3.4, 1.5 Hz), 6.98 – 6.91 (1H, m), 6.87 (1H, ddt, J = 12.4, 8.3, 2.6 Hz), 6.40 – 6.33 (1H,
m), 6.28 (1H, dd, J = 3.6, 3.0 Hz), 6.14 (1H, pd, J = 7.1, 0.9 Hz), 4.38 (1H, d, J = 26.3 Hz), 3.99 – 3.84 (3H, m), 3.71 (1H, ddq, J = 10.0,
8.7, 7.0 Hz), 1.90 (3H, dd, J = 7.2, 6.2 Hz), 1.14 (3H, td, J = 7.1, 0.5 Hz), 1.10 (3H, t, J = 7.1 Hz).13C NMR (101 MHz, CDCl3) δ 159.1 –
156.3 (CF, m), 153.5 – 150.5 (CF, m), 131.0 (C, d, J = 3 Hz), 126.7 – 126.2 (C, m), 122.4 (CH, d, J = 13 Hz), 121.5 (C, m), 121.2 (C, d, J
= 12 Hz), 119.6 (CH, d, J = 17 Hz), 113.2 (CH, ddd, J = 23, 5, 4 Hz), 111.0 (CH, d, J = 4 Hz), 104.9 (CH), 104.5 (CH, td, J = 26, 4 Hz),
63.0 (CH2, d, J = 7 Hz), 62.8 (CH2, d, J = 8 Hz), 41.4 (CHP, d, J = 135Hz), 16.3 (CH3, d, J = 6 Hz), 16.2 (CH3, d, J = 6 Hz), 14.0 (CH3, d,
J = 3 Hz). 31P NMR (CDCl3, 283 MHz) δ 20.62 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ116.3 (m), ꢀ121.3 (m). IR (neat, cmꢀ1) 2981 (w),
1603 (w), 1505 (s), 1304 (m), 1247 (m), 1124 (m), 1019 (s), 968 (m), 710 (m), 582 (m). LCꢀMS (ESI) m/z = 368.5 (M+H). HRꢀMS
(TOFꢀESI+) calculated for C18H21NO3PF2 368.1227, found 368.1226 (ꢁ = ꢀ0.3 ppm).
Diethyl (7,9-difluoro-4-(1-phenylethyl)pyrrolo[1,2a]quinolin-5-yl)phosphonate, (1r): 0.1 g (10%, 3 mmol scale).
1H NMR (400 MHz, CDCl3) δ 8.64 (1H, dt, J = 12.1, 2.3 Hz), 8.18 (1H, dd, J = 2.8, 1.5 Hz), 7.38 – 7.26 (4H, m), 7.22 – 7.14 (1H, m),
7.07 (1H, ddd, J = 13.3, 7.6, 2.8 Hz), 6.60 (1H, dd, J = 4.2, 2.9 Hz), 6.38 (1H, d, J = 4.2 Hz), 6.06 (1H, q, J = 7.0 Hz), 4.39 – 4.00 (4H, m),
1.88 (3H, d, J = 7.1 Hz), 1.37 (3H, t, J = 7.1 Hz), 1.27 (3H, t, J = 7.0 Hz). 13C NMR (175 MHz, CDCl3) δ 157.2 (CF, dd, J = 242, 14 Hz),
153.5 – 151.5 (CF, m), 149.7 (C, d, J = 12 Hz), 144.2 (C), 128.2 (2CH), 126.7 (2CH), 125.7 (CH), 119.6 (CH, d, J = 25 Hz), 119.1 (C, m),
113.5 (CH, d, J = 5 Hz), 111.6 (CP, d, J = 190 Hz), 110.3 (CH, dt, J = 26, 3 Hz), 110.2 (CH), 103.2 (CH, dd, J = 28, 26 Hz), 62.2 (CH2, d,
J = 3 Hz), 62.2 (CH2, d, J = 3 Hz), 39.6 (CH, d, J = 5 Hz), 18.5 (CH3, d, J = 1 Hz), 16.3 (CH3, d, J = 7 Hz), 16.2 (CH3, d, J = 7 Hz), 2 C
resonances not found. 31P NMR (CDCl3, 283 MHz) δ 18.56 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ115.4 (m), ꢀ118.4 (m). IR (neat, cmꢀ1)
2981 (w), 1606 (w), 1508 (s), 1248 (m), 1049 (m), 1020 (s), 964 (m), 725 (s), 700 (s), 602 (m), 571 (m). LCꢀMS (ESI) m/z = 444.5
(M+H). HRꢀMS (TOFꢀES+) calculated for C24H25NO3PF2 444.1540, found 444.1542 (ꢁ = 0.5 ppm).
(E)-Diethyl (7,9-difluoro-4-(1-phenylethylidene)-4,5-dihydropyrrolo[1,2-a]quinolin-5-yl)phosphonate, (1r’): 0.9 g (64%, 3 mmol scale).
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1H NMR (400 MHz, CDCl3) δ 7.35 – 7.27 (4H, m), 7.22 – 7.17 (2H, m), 7.03 – 6.96 (1H, m), 6.90 (1H, ddt, J = 12.2, 8.4, 2.6 Hz), 6.00
(1H, dd, J = 3.8, 3.0 Hz), 5.26 – 5.18 (1H, m), 4.52 (1H, d, J = 25.6 Hz,), 4.01 – 3.84 (3H, m), 3.70 (1H, ddq, J = 10.1, 8.7, 7.1 Hz), 2.26
(3H, d, J = 5.3 Hz), 1.17 (3H, t, J = 7.1 Hz), 1.14 (3H, t, J = 7.1 Hz). 13C NMR (175 MHz, CDCl3) δ 158.8 – 157.0 (CF, m), 153.0 – 150.9
(CF, m), 144.5 (C, d, J = 4 Hz), 135.4 (C, d, J = 13 Hz), 128.7 (C, d, J = 3 Hz), 128.5 (2CH), 128.2 (2CH, d, J = 4 Hz), 127.2 (C, t, J = 9
Hz), 126.9 (CH), 121.7 (C, d, J = 10 Hz), 118.6 (CH, d, J = 16 Hz), 116.6 (C, d, J = 11 Hz), 113.3 – 112.6 (CH, m), 111.0 (CH), 110.6
(CH), 104.9 – 104.1 (CH, m), 62.8 (2CH2, app t, J = 8 Hz), 43.7 (CHP, d, J = 135 Hz), 22.2 (CH3, d, J = 3 Hz), 16.4 (CH3, d, J = 6 Hz),
16.3 (CH3, d, J = 6 Hz). 31P NMR (CDCl3, 283 MHz) δ 20.91 (s). 19F NMR (CDCl3, 367 MHz) δ ꢀ116.0 (m), ꢀ121.9 (m). IR (neat, cmꢀ
1): 2983 (w), 1609 (w), 1508 (s), 1250 (m), 1120 (m), 1022 (s), 966 (m), 700 (m), 602 (m). LCꢀMS (ESI) m/z = 444.7 (M+H). HRꢀMS
(TOFꢀES+) calculated for C24H25NO3PF2 444.1540, found 444.1527 (ꢁ = ꢀ2.9 ppm).
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ASSOCIATED CONTENT
Supporting information containing General experimental, emission spectra from flow reactions, spectra, and crystallographic data (CCDCꢀ
1411501 and CCDCꢀ1141502) is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
i.r.baxendale@durham.ac.uk
ACKNOWLEDGMENT
Financial support from the Royal Society (to MB and IRB; UF130576) is gratefully acknowledged. Furthermore, we are grateful to Dr
Dmitry Yufit (Durham University, Department of Chemistry) for solving the Xꢀray structures and Duncan Guthrie as well as Stacey Crane
(Vapourtec) for lending the photoꢀspectrometer and helpful discussions.
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(15) By passing clean product 1o through the flow reactor both under thermal and photochemical conditions significant decomposition of 10ꢀ
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(16) In parallel to these experiments a number of common Lewis acids was screened as additives for challenging cyclisation reactions, however,
the preliminary data obtained was not promising and hence not followed further.
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