Tandem processes identified from reaction screening: Nucleophilic addition to aryl N -phosphinylimines employing La(III)-TFAA activation

Article abstract of DOI:10.1021/ja100346w

Reaction screening of nucleophilic reaction partners for addition to N-diphenylphosphinylimines employing lanthanum(III) triflate as a catalyst and trifluoroacetic anhydride (TFAA) as an activator is reported. A number of tandem processes leading to novel chemotypes including aza-Prins/intramolecular Friedel-Crafts annulations have been identified, and both reaction scope and mechanism further investigated.

Full text of DOI:10.1021/ja100346w

Published on Web 04/15/2010
Tandem Processes Identified from Reaction Screening:
Nucleophilic Addition to Aryl N-Phosphinylimines Employing
La(III)-TFAA Activation
Hidenori Kinoshita, Oscar J. Ingham, Winnie W. Ong, Aaron B. Beeler, and
John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment
(CMLD-BU), Boston UniVersity, Boston, Massachusetts 02215
Received January 14, 2010; E-mail: porco@bu.edu
Abstract: Reaction screening of nucleophilic reaction partners for addition to N-diphenylphosphinylimines
employing lanthanum(III) triflate as a catalyst and trifluoroacetic anhydride (TFAA) as an activator is reported.
A number of tandem processes leading to novel chemotypes including aza-Prins/intramolecular Friedel-Crafts
annulations have been identified, and both reaction scope and mechanism further investigated.
Scheme 1. Friedel-Crafts and Aza-ene Reactions with 1
Introduction
We recently reported Friedel-Crafts and aza-ene reactions
between N-phosphinylimines1 and carbon nucleophiles using a
La(OTf)3 ·nH2O/TFAA activation protocol (Scheme 1).2 For
example, treatment of N-diphenylphosphinylimine 1 and furan
2
with trifluoroacetic anhydride (TFAA) and catalytic
La(OTf)3 ·nH2O under microwave irradiation led to production
of Friedel-Crafts product 3. Alternatively, use of methylenecy-
clopentene 4 as a nucleophile led to homoallylic amide 5 in
good yield (82%). To study the scope and limitations of these
reactions and expand their utility, we undertook reaction
screening3 of a panel of nucleophilic reaction partners. Herein,
we report the results of this study, identification of a number
of tandem reaction processes producing novel chemotypes, and
follow-up studies to investigate the reaction scope and mechanism.
ultraperformance liquid chromatography (UPLC)-MS/ELS.6
Based on analytical data,5 decisions to conduct scale-up reactions
to elucidate products were made. Reactions were scaled up 10-
fold (0.15 mmol), and the products isolated. Results of initial
reaction screening indicated that 17 of 33 reactions afforded
major products; 9 of 17 reactions afforded products correspond-
ing to adducts between the N-phosphinylimine substrate and
alkene reaction partner. Based on the screening results, products
were grouped into three major classes. The first reaction type
identified in the screen involved aza-Friedel-Crafts reactions
(Table 1).7 Thiophene 6 afforded the aza-Friedel-Crafts product
7 (Table 1, entry 1) as expected7d in contrast to pyrrole which
was unreactive under the reaction conditions (data not shown).
Interestingly, 2-methylindene 8 also provided aza-Friedel-
Crafts product 9 in 62% yield (Table 1, entry 2). Cyclopropy-
lbenzene 12 provided product 13 in 33% yield along with the
cyclic product 14 (6%). In this case, cyclopropane ring cleavage
of 12 to afford trans-ꢀ-methylstyrene occurred in situ under
Results and Discussion
For the reaction screen, 33 nucleophilic reaction partners were
selected with a number of entries based on reported imino-ene
reactions (Figure 1).4 Reactions were conducted using N-
phosphinylimine 1 (0.015 mmol) as a substrate, La(OTf)3 ·nH2O
(20 mol %), 5.0 equiv of TFAA (0.075 mmol), and 100 µL of
CH3CN under microwave irradiation at 80 °C.5 After the
reaction (10 min), the mixtures were filtered and evaluated using
(1) Weinreb, S. M.; Orr, R. K. Synthesis 2005, 1205.
(2) Ong, W. W.; Beeler, A. B.; Kesavan, S.; Panek, J. S.; Porco, J. A., Jr.
Angew. Chem., Int. Ed. 2007, 46, 7470.
(3) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2007, 129, 1413.
(4) For examples of imino-ene reactions, see: (a) Drury, W. J., III.; Ferraris,
D.; Cox, C.; Young, B.; Lectka, T. J. Am. Chem. Soc. 1998, 120,
11006. (b) Ferraris, D.; Young, B.; Cox, C.; Dudding, T.; Drury, W. J.,
III.; Ryzhkov, L.; Taggi, A. E.; Lectka, T. J. Am. Chem. Soc. 2002,
124, 67. (c) Caplan, N. A.; Hancock, F. E.; Bulman, P. C.; Hutchings,
G. J. Angew. Chem., Int. Ed. 2004, 43, 1685. (d) Aburel, P. S.; Zhuang,
W.; Hazell, R. G.; Jorgensen, K. A. Org. Biomol. Chem. 2005, 3,
2344. (e) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem.,
Int. Ed. 2006, 45, 2254.
(6) (a) Mazzeo, J. R.; Neue, U. D.; Kele, M.; Plumb, R. S. Anal. Chem.
2005, 77, 460 A. (b) Nova´kova´, L.; Matysova´, L.; Solich, P. Talanta
2006, 68, 908.
(7) For recent examples of aza-Friedel-Crafts alkylations, see: (a) Saaby,
S.; Bayo´n, P.; Aburel, P. S.; Jørgensen, K. A. J. Org. Chem. 2002,
67, 4352. (b) Luo, Y.; Li, C.-J. Chem. Commun. 2004, 1930. (c)
Esquivisas, J.; Arraya´s, R. G.; Carretero, J. C. Angew. Chem., Int.
Ed. 2006, 45, 629. (d) Jia, Y.-X.; Xie, J.-H.; Duan, H.-F.; Wang, L.-
X.; Zhou, Q.-L. Org. Lett. 2006, 8, 1621. (e) Liu, C.-R.; Li, M.-B.;
Yang, C.-F.; Tian, S.-K. Chem. Commun. 2008, 1249.
(5) See Supporting Information for complete experimental details.
9
6412 J. AM. CHEM. SOC. 2010, 132, 6412–6418
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Tandem Processes Identified from Reaction Screening
A R T I C L E S
Table 2. Aza-ene Reactionsa
Figure 1. Reaction Partners.
Table 1. Aza-Friedel-Crafts Reactionsa
a N-Phosphinylimine 1 (0.152 mmol), alkene (0.76 mmol, 5 equiv),
and TFAA (0.76 mmol, 5 equiv) were used with 0.038 mmol (25 mol
%) of La(OTf)3 ·nH2O in 0.7 mL of CH3CN. b Isolated yield after silica
gel chromatography. c Dr values and E/Z ratios determined by 1H NMR
analysis.
Second, a number of alkenes afforded aza-ene products in
good to excellent yields (Table 2). Reactions utilizing methylene
cyclohexane (18) and 2-methyl-2-propene (27) afforded cyclic
products 20 and 29 which were obtained in 10% and 49% yields,
respectively, along with aza-ene products 19 and 28 (Table 2,
entries 1 and 5). These observations suggested that reactions
may proceed through a stepwise aza-Prins9-intramolecular
Friedel-Crafts cyclization which may be operative if the
(8) For formation of trans-ꢀ-methylstyrene from cyclopropyl-benzene, see:
Mochalov, S. S.; Gazzaeva, R. A.; Fedotov, A. N.; Shabarov, Y. S.;
Zefirov, N. S. Chem. Heterocycl. Compd. 2003, 39, 794.
(9) For aza-Prins reactions, see: (a) Dobbs, A. P.; Guesne´, S. J. J.; Coles,
S. J.; Hursthouse, M. B. Synlett 2003, 1740. (b) Hanessian, S.;
Tremblay, M.; Petersen, J. F. W. J. Am. Chem. Soc. 2004, 126, 6064.
(c) Liu, J.; Hsung, R. P.; Peters, S. D. Org. Lett. 2004, 6, 3989. (d)
Hanessian, S.; Tremblay, M.; Marzi, M.; Del Valle, J. R. J. Org. Chem.
2005, 70, 5070. (e) Armstrong, A.; Shanahan, S. E. Org. Lett. 2005,
7, 1335. (f) Sarkar, T. K.; Hazra, A.; Gangopadhyay, P.; Panda, N.;
Slanina, Z.; Lin, C.-C.; Chen, H.-T. Tetrahedron 2005, 61, 1155. (g)
Shimizu, M.; Baba, T.; Toudou, S.; Hachiya, I. Chem. Lett. 2007, 36,
12. (h) Murty, M. S. R.; Ram, K. R.; Yadav, J. S. Tetrahedron Lett.
2008, 49, 1141. (i) Yadav, J. S.; Reddy, B. V. S.; Chaya, D. N.; Kumar,
G. G. K. S. N.; Aravind, S.; Kunwar, A. C.; Madavi, C. Tetrahedron
Lett. 2008, 49, 3330. (j) Lee, H. M.; Nieto-Oberhuber, C.; Shair, M. D.
J. Am. Chem. Soc. 2008, 130, 16864.
a N-Phosphinylimine 1 (0.152 mmol), ArH (0.76 mmol, 5 equiv), and
TFAA (0.76 mmol, 5 equiv) were incubated with 0.038 mmol (25 mol
%) of La(OTf)3 ·nH2O in 0.7 mL of CH3CN. b Isolated yield after silica
gel chromatography.
the reaction conditions; subsequent reaction with N-phosphi-
nylimine 1 afforded indane product 14, the same product
observed employing trans-ꢀ-methylstyrene (Vide infra).8 In
addition, anisole 15 led to Friedel-Crafts addition to afford the
para- and ortho- isomers 16 and 17 (Table 1, entry 5).
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Kinoshita et al.
Table 3. Evaluation of N-Phosphinylimine Substitutiona
Table 4. Tandem Aza-Prins/Friedel-Crafts Reactions
a 2 equiv of 18, 1.5 equiv of TFAA, and 25 mol % La(OTf)3 ·nH2O
in 0.7 mL of CH3CN.
carbocation intermediate generated after the initial imino-ene
reaction was appropriately stabilized.10 Although tandem Prins/
Friedel-Crafts reactions have precedent,11 successive use of
aza-Prins and intramolecular Friedel-Crafts reactions are less
well developed.9
As part of the study, we also evaluated a series of N-
phosphinylimines 30-36 using methylenecyclohexane (18) as
an alkene partner (Table 3). Using standard conditions, aza-
Prins reactions proceeded in high yield to afford adducts 37-43
with the exception of 3,5-dimethoxy-N-phosphinylimine (33)
(Table 3, entry 4). The major product in this case was the
hydrolysis product 3,5-dimethoxybenzaldehyde. In all cases,
spirocyclic ring formation (cf. Table 2, entry 1) was not
observed.
Our reaction screening results also revealed that styrenic
reaction partners underwent tandem aza-Prins/Friedel-Crafts
reactions affording polycyclic scaffolds, likely due to aromatic-
stabilized carbocationic intermediates (44, Table 4) which
facilitate the Friedel-Crafts cyclization. Accordingly, we further
evaluated various styrenic partners. Follow-up reactions were
initially carried out employing conditions utilized for the reaction
screen (cf. Table 2).12 Reaction with 1-phenyl-1-cyclohexene
(45) afforded both the cyclized product 46 (70% yield, dr )
8:1) in which the ring junction proton is syn to the trifluoro-
acetamide and the uncyclized, trisubstituted alkene 47 (29%
yield, dr ) 10:1) favoring the “anti” relative stereochemistry
(Table 4, entry 1).5,13 Lowering the reaction temperature to 0
°C had a strong effect on the diastereoselectivity of cyclized
and uncyclized products (dr ) 17:1 and >20:1, respectively).
(10) For the formal [3 + 2] addition of alkenes to benzhydrol cations, see:
(a) Lantan˜o, B.; Aguirre, J. M.; Finkielsztein, L.; Alesso, E. N.; Brunet,
E.; Moltrasio, G. Y. Synth. Commun. 2004, 34, 625. (b) Lantan˜o, B.;
Aguirre, J. M.; Ugliarolo, E. A.; Benegas, M. L.; Moltrasio, G. Y.
Tetrahedron 2008, 64, 4090.
a Isolated yields. b Major diastereomer shown. c Diastereomeric ratios
determined by 1H NMR analysis. d Styrene (1.2 equiv), µWave, 80 °C,
25 min. e Styrene (1.2 equiv), 0 °C, 12 h. f Styrene (1.2 equiv), µWave,
60 °C, 25 min.
(11) (a) Basavaiah, D.; Sharada, D. S.; Veerendhar, A. Tetrahedron Lett.
2004, 45, 3081. (b) Yang, X.-F.; Wang, M.; Zhang, Y.; Li, C.-J. Synlett
2005, 12, 1912. (c) Tian, X.; Jaber, J. J.; Rychnovsky, S. D. J. Org.
Chem. 2006, 71, 3176. (d) Basavaiah, D.; Reddy, K. R. Org. Lett.
2007, 9, 57.
Reaction with indene (48) (entry 2) afforded the cyclized
tetrahydroindanoindane derivative 49 exclusively in moderate
diastereoselectivity (71% yield, dr ) 4:1). Reaction with 1,2-
dihydronaphthalene (50) affords a mixture of tetracycle 51 in
83% yield (dr ) 5:1) along with the acyclic, conjugated product
(12) Attempts to reduce catalyst loading resulted in significantly lower
yields. For example, use of 10 mol% La(OTf)3 afforded a 23% isolated
yield of 46.
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A R T I C L E S
Table 5. Use of Alternative N-Phosphinyliminesa b
,
a N-Phosphinylimine (0.152 mmol), La(OTf)3 ·nH2O (25 mol %), TFAA (1.5 equiv), and 2.0 equiv of 1-phenyl-1-cyclohexene in 0.7 mL of solvent.
Reaction time at rt or 0 °C was 12 h. b Relative stereochemistry of the major diastereomer shown.
52 (15% yield) (entry 3). Use of 1-(4-methylphenyl)-1-cy-
clobutene (53)14 afforded the benzobicyclo [3.2.0] derivative
54 in good yield but in low diastereoselectivity (82% yield, dr
) 1.7:1, entry 4) slightly favoring the “syn” product. Reaction
with 1-phenyl-1-cycloheptene 55 afforded the cyclized product
56 in excellent yield (90% yield, dr ) 1.7:1) along with a trace
amount of acyclic product 57. Reactions with styrenes 58 and
60 afforded high yields and low diastereoselectivity with
exclusive formation of cyclized products 59 and 61. Interest-
ingly, reaction with R-methyl styrene 62 afforded the cyclized
product 63 which contains an all-carbon quaternary center (66%
yield, dr ) 1.5:1).
(CH3NO2)15 it may be possible to obtain higher levels of
cyclized products. Reaction of 45 with N-phosphinylimine 1
utilizing CH3NO2 as solvent at room temperature did not have
a dramatic effect on the yield of cyclized product but did
negatively affect the diastereomeric ratio (5:1) (entry 1).
Reaction with dimethoxy-N-phosphinylimine 30 in CH3CN
afforded the cyclized product 64 in 47% yield (dr ) 8:1) along
with acyclic product 65 in 46% yield (d.r. ) 2.5: 1) (entry 2).
However, use of CH3NO2 as solvent significantly increased the
isolated yield of 64 albeit in lower diastereoselectivity which
could be increased by lowering the temperature to 0 °C. We
observed a similar increase in cyclization products utilizing
CH3NO2 in reaction with N-phosphinylimines 31 and 34. We
also observed a noticeable reduction of cyclized products as
We next evaluated a number of substituted N-phosphi-
nylimines as reaction partners (Table 5). We anticipated
that by utilizing the cation-stabilizing solvent nitromethane
(15) (a) Bra˜tulescu, G.; Bigot, Y. L.; Delmas, M. Synth. Commun. 2001,
31, 3309. (b) Grundl, M. A.; Kaster, A.; Beaulieu, E. D.; Trauner, D.
Org. Lett. 2006, 8, 5429. (c) Li, S.; Chiu, P. Tetrahedron Lett. 2008,
49, 1741.
(13) Relative stereochemistry was determined by NMR and X-ray crystal-
lographic analyses.
(14) Juteau, H.; Gareau, Y. Synth. Commun. 1998, 28, 3795.
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Scheme 2. Synthesis of an Alkaloidal Core Structure
Figure 3. DFT transition state calculations.
17
luoroacetamide 20 with NaBH4 under microwave irradiation
afforded benzylic amine 77 (92% yield). The fused piperidine
ring was constructed utilizing a modified Pomeranz-Fritsch-
Bobbitt reaction18 which was initiated by alkylation of amine
77 with 2-bromoacetaldehyde diethyl acetal (78) to afford amino
acetal 79 (53% yield). Cyclization under acidic conditions,
followed by subsequent dehydroxylation (TFA/NaBH4), affords
isoquinoline 80 in 54% yield.
Scheme 3. Equilibration of Acyclic Products 73b, 73, and 81
To probe the mechanistic pathway for the tandem aza-Prins/
Friedel-Crafts alkylation process, we conducted a number of
control experiments. The first experiment involved reaction of
acyclic products 73 and 73b which are unable to further cyclize
(Scheme 3). When an enriched mixture of stereoisomer 73b
(dr ) 9:1) was incubated in the presence of La(OTf)3 and TFAA
and irradiated in the microwave, we observed an equilibration
of the products to afford both diastereomers and the alternative
elimination product (73b/73/81 ) 1:0.6:0.7). In a similar fashion
treatment of an enriched sample of stereoisomer 73 led to
equilibration affording the same three products (0.5:1:0.4).
Additional experiments involved incubation of the acyclic
stereoisomer 47 in CH3NO2 under microwave irradiation
(Scheme 4). We observed the formation of cyclized products
46 and 46b (3:1) indicating a similar equilibration prior to
cyclization. We also carried out experiments to determine if
cyclized products such as 46 and 46b are capable of equilibration
Via retro-Friedel-Crafts reactions.19 Under standard reaction
conditions in the microwave at 80 °C, there was no change in
the product distribution as well as no change when the product
was incubated in the presence of TFA. Based on these
observations, we believe that acyclic products such as 47 and
73 are capable of isomerization allowing for thermodynamic
equilibration.20
Scheme 4. Equilibration of Acyclic Products 46 and 46b
the aryl ring of the N-phosphinylimine became less electron
rich. For example, 4-methoxyphosphinylimine substrate (32)
afforded exclusively the acyclic product 70 in good yield and
low diastereoselectivity using CH3CN as the solvent. Efforts to
promote cyclization with CH3NO2 were unsuccessful yielding
only 70 (dr ) 2.3:1). Less nucleophilic aryl N-phosphinylimines
(entries 6-8) afforded similar results as observed for substrate
32 with a slight preference observed for the “syn” diastereomer
(cf. Table 5, entry 5). Utilization of trans-cinnamaldehyde-
derived phosphinyl imine 75 affords exclusively acyclic adduct
76 (dr ) 1:1) in excellent yield (95%).
We also evaluated solvent effects for the tandem reaction
employing methylenecyclohexane (18) and N-phosphinylimine
1 (Scheme 2). As anticipated, use of CH3NO2 as solvent led to
increased formation of spirocycle 20 (52%). In an effort to
exploit the rapid synthesis of this spirocyclic scaffold, we
envisioned the synthesis of the tetracyclic framework of the
isoquinoline alkaloid litsericine (inset).16 Deprotection of trif-
Utilizing computational analysis (B3LYP/6-31G(d)) of ste-
reoisomeric carbocation intermediates 82 and 83 (Figure 3), we
have determined that the “syn” carbocation is thermodynamically
favored by 2.2 kcal/mol.5 Structural optimizations of transition
states for Friedel-Crafts alkylation leading to both cyclization
(17) Kudzin, Z. H.; Ływ˙ a, P.; Łuczak, J.; Andrijewski, G. Synthesis 1997,
44.
(18) Grajewska, A.; Rozwadowska, M. D. Tetrahedron: Asymmetry 2007,
18, 557.
(19) Snyder, S. A.; Breazzano, S. P.; Ross, A. G.; Lin, Y.; Zografos, A. L.
J. Am. Chem. Soc. 2009, 131, 1753.
(20) Initial studies to probe the mechanism of equilibration were carried
out. An attempted crossover experiment utilizing compound 73 and a
differentially substituted derivative under the aza-Prins/Friedel-Crafts
conditions (La(OTf)3/TFAA) did not lead to observable crossover
indicating that the retro-aza-Prins process is likely not operative.
(16) (a) Nakasato, T.; Asada, S. Yakugaku Zasshi 1966, 86, 134. (b)
Nakasato, T.; Asada, S. Yakugaku Zasshi 1966, 86, 1205. (c) Lu, S.-
T.; Su, T.-L.; Wang, E.-C. J. Chin. Chem. Soc. 1975, 22, 349.
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A R T I C L E S
Figure 5. DFT structures for carbocationic intermediates en route to 90.
(a) DFT optimized structure for “syn” carbocation 91. (b) DFT optimized
structure for the “anti” carbocation 92.
Figure 4. Transition states for Friedel-Crafts cyclization.
Scheme 5. Tandem Reactions with 1,3-Dienes
Scheme 6. A Bis-Indane from Reaction with Indene
transformation with 2,3-dimethyl diene 88 to afford the ben-
zylcycloheptene product 89 in 61% yield.
In follow-up studies, we noted the formation of a new product
in the reaction of N-phosphinylimine 31 and indene 48 (Scheme
6). X-ray crystal analysis revealed the structure to be the bis-
indane 905 which was produced in 20% yield as a single
diastereomer. We propose that this product is obtained in a
related tandem aza-Prins/alkene addition/Friedel-Crafts process
to afford a complex, hexacyclic framework bearing five contigu-
ous stereocenters. An intriguing aspect of this reaction is the
formation of a single stereoisomer. To understand the stereo-
chemical outcome, we conducted computational analysis of
proposed intermediates in the reaction pathway (Figure 5). The
C1 and C2 relative stereochemistry are likely derived from
preferential addition of the second indene to the “syn” carboca-
tionic intermediate 91. DFT structural optimization of the
intermediates reveals that the “anti” intermediate 92 is situated
such that the carbonyl oxygen of the amide and the carbocation
have a significant n-p interaction delocalizing the positive
charge through an acetoxonium-like species (Figure 5).23
Through this interaction, the carbocation begins to take on sp3
character rendering 92 less reactive toward addition of the
second indene. These models also indicate that only the si face
of carbocation 91 is available for addition of the second indene,
thus establishing the C3 stereocenter.
products were also performed (Figure 3).5 TS1 derived from
the “syn” carbocation requires 8.6 kcal/mol while TS2 derived
from the “anti” carbocation requires 11.5 kcal/mol. Closer
examination of both TS1 and TS2 reveals that the conformation
of the cyclohexane bearing the carbocation may be responsible
for the energy differences (Figure 4). TS1 is in a preferred chair
conformation while TS2 adopts an energetically disfavored boat
conformation. Overall, our computational results suggest that
the reaction with dimethoxy-substrate 30 which affords high
diastereoselectivity may likely be under thermodynamic equili-
bration of the stereoisomeric cationic intermediates. Further-
more, there is also strong evidence for a kinetic preference for
cyclization of one stereoisomer which likely improves the
resulting diastereoselectivity. In a similar manner, lower dias-
tereoselectivities, as is the case for the reaction with cyclohep-
tene 55 (Table 4), are likely due to each stereoisomer having a
similar energy barrier for cyclization as supported by transition
state calculations.5
A related tandem process was also discovered in the reaction
screen involving 2,3-diphenyl diene 84 which afforded indene
85 and the formal [4 + 3] cyclization product benzocycloheptene
86 in good overall yields (Scheme 5).21 It appears that the allylic
carbocation intermediate 87 generated after initial aza-Prins
addition22 may be trapped by intramolecular Friedel-Crafts
cyclization with either aryl group. We also observed a similar
We propose that the syn relationship of C3 and C4 may be
derived from the inability of the anti counterpart 93 to undergo
cyclization (C5-C6 distance ) 4.5 Å) thus leading to polym-
erization or elimination (Figure 6). The syn intermediate 94
(22) For stepwise addition of dienes to N-aryl imines, see: Hermitage, S.;
Howard, J. A. K.; Jay, D.; Pritchard, R. G.; Probert, M. R.; Whiting,
A. Org. Biomol. Chem. 2004, 2, 2451.
(21) For reviews of [4 + 3] cyclizations, see: (a) Harmata, M. Acc. Chem.
Res. 2001, 34, 595. (b) Harmata, M.; Rashatasakhon, P. Tetrahedron
2003, 59, 2371.
(23) Woodward, R. B.; Brutcher, F. V., Jr. J. Am. Chem. Soc. 1958, 80,
209. (b) Norrild, J. C.; Pedersen, C. A.; Sotofte, I. Carbohydr. Res.
1997, 297, 261.
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obtain the cyclic products through intramolecular Friedel-Crafts
cyclization. We also achieved spirocycle formation through
tandem aza-Prins Friedel-Crafts reactions employing exocyclic
alkenes as reaction partners and nitromethane as the solvent
which has been found to stabilize carbocation intermediates.
Mechanistic experiments support thermodynamic equilibration
of stereoisomeric cationic intermediates as well as different
barriers for Friedel-Crafts cyclization to establish acyclic-cyclic
product distributions and stereochemistries. Further studies
involving reaction screening to identify novel reactions and
chemotypes as well as use of the polycyclic scaffolds obtained
in library synthesis applications are ongoing in our laboratories
and will be reported in due course.
Acknowledgment. This work was generously supported by the
NIGMS CMLD Initiative (P50 GM067041). We thank Dr. Emil
Lobkovsky (Cornell University) for X-ray crystal structure analysis,
Dr. Paul Ralifo (Boston University) for assistance with NMR, and
Professors Richard Johnson (University of New Hampshire), James
Panek, John Snyder, Scott Schaus, and Corey Stephenson (Boston
University) for helpful discussions. NMR (CHE-0619339) and MS
(CHE-0443618) facilities at Boston University are supported by
the NSF and computational resources were provided by the Boston
University Scientific Computing and Visualization Center. We also
thank Waters Corporation and CEM Corporation for assistance with
instrumentation.
Figure 6. DFT structures for bis-indane carbocation intermediates. (a) DFT
model of the C3/C4 syn carbocation intermediate 93. (b) DFT model of
the C3/C4 anti carbocation intermediate 94.
appears to be restricted to cyclization at the si face (opposite to
the C4 hydrogen) leading to the observed relative stereochem-
istry at C5.
Conclusion
Supporting Information Available: Experimental procedures
and characterization data for all new compounds, including
X-ray structure analyses of compounds 46, 49, 74, 86, 90 (PDF).
X-ray crystallographic data (CIF). This material is available free
of charge via the Internet at http://pubs.acs.org.
We have utilized reaction screening to study additions of
nucleophilic reaction partners to N-diphenylphosphinylimines
using La(OTf)3 ·nH2O/TFAA activation. Based on screening
results, we identified tandem aza-Prins/intramolecular Friedel-
Crafts reactions between N-phosphinylimines and a number of
styrenic and diene reaction partners which produce complex
polycyclic frameworks, many bearing the privileged diaryl-
methane pharmacophore.24 The scope and limitations of the
process were studied and have led to the finding that substituents
on the aromatic ring of N-phosphinylimines were crucial to
JA100346W
(24) For a review of privileged structures, see: Mason, J. S.; Morize, I.;
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