Synthesis of Substituted γ- and δ-Lactams via Pd-Catalyzed Alkene Carboamination Reactions

Article abstract of DOI:10.1021/acs.joc.7b00041

The synthesis of substituted γ- and δ-lactams via palladium-catalyzed alkene carboamination reactions between aryl halides and alkenes bearing pendant amides is described. The substrates for these reactions are generated in 1-3 steps from commercially ava

Full text of DOI:10.1021/acs.joc.7b00041

Note
pubs.acs.org/joc
Synthesis of Substituted γ- and δ‑Lactams via Pd-Catalyzed Alkene
Carboamination Reactions
Jordan R. Boothe, Yifan Shen, and John P. Wolfe*
Department of Chemistry, University of Michigan, 930 North University Avenue, Ann Arbor, Michigan 48109-1055, United States
S
* Supporting Information
ABSTRACT: The synthesis of substituted γ- and δ-lactams via
palladium-catalyzed alkene carboamination reactions between aryl
halides and alkenes bearing pendant amides is described. The
substrates for these reactions are generated in 1−3 steps from
commercially available materials, and products are obtained in
good yield with up to >20:1 diastereoselectivity. The stereo-
chemical outcome of the alkene addition is consistent with a mechanism involving anti-aminopalladation of the alkene.
γ-Lactams (pyrrolidin-2-ones) are a common motif present in a
variety of biologically active compounds and natural products
including Clausenamide (1, nootropic agent)1,2 and strepto-
pyrrolidine (2, angiogenesis inhibitor)3 (Figure 1). Given the
Scheme 1. Pd-Catalyzed Alkene Carboamination of Urea vs
Amide
Figure 1. Biologically active 4-benzylpyrrolidin-2-one derivatives.
product 8 and desired product 9 in an unfavorable 2.3:1
ratio.20,21
Given our unsatisfactory results for the conversion of 6 to 9,
we were quite surprised when Cacchi reported a series of Pd-
catalyzed carboamination reactions of 10 that afford substituted
(5R,7aR)-5-aryl hexahydropyrrolizidin-3-ones 11 (Scheme 2).22
significance of these molecules, a variety of synthetic techniques
have been employed for their construction4 including alkene
hydroamination,5,6 intramolecular N-arylation of amides,7 N-
centered radical cyclizations of 4-pentenamides,8,9 four-
component coupling reactions,10 and reductive amination
strategies.11
Over the past 12 years our group has developed a series of
palladium-catalyzed alkene carboamination reactions between
alkenes bearing pendant nitrogen nucleophiles and aryl/alkenyl
halides/triflates.12,13 These transformations generate both a C−
N and a C−C bond during the ring-forming step and afford the
heterocyclic products in generally good chemical yield, typically
with high diastereoselectivity. For example, treatment of N-allyl
urea 3 with 4 in the presence of a Pd/Xantphos catalyst
afforded 5 in 75% yield (Scheme 1, eq 1).14−16 We felt that this
approach could be employed for the construction of γ-lactams
from N-protected 4-pentenamides (Scheme 1, eq 2). However,
although we have successfully employed a number of different
nitrogen nucleophiles in these reactions, including anilines,17
guanidines,18 carbamates,19 and N-acylated amines,19 our early
efforts to extend this method to 4-pentenamides were largely
unsuccessful as products were formed in very low yields due to
competing Heck arylation of the alkene. For example attempts
to couple amide 6 with 7 under conditions that proved optimal
with urea substrate 3 afforded a mixture of Heck arylation
Scheme 2. Cacchi’s Pd-Catalyzed Alkene Carboamination of
Lactam 10
Although only a single alkene substrate was examined in these
transformations, the coupling of 10 with a range of different
aryl halides provided the bicyclic lactam products 11 in
generally good yield (41−90%). Given Cacchi’s success with
this system, coupled with the fact that the scope of the amide
carboamination reactions (with respect to amide substrate
structure) was not fully explored, we elected to re-examine Pd-
Received: January 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.7b00041
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The Journal of Organic Chemistry
Note
catalyzed alkene carboamination reactions of pentenamide-
derived substrates related to 6.
In order to develop satisfactory conditions for Pd-catalyzed
alkene carboamination reactions of pentenamide derivatives we
explored the coupling of N-PMP-substituted pentenamide
substrate 12a with bromobenzene (Table 1).23 We first
ultimately arrive at optimized conditions that employed PdBr2/
XPhos as the catalyst, LiOtBu as the base, and PhCF3 as the
solvent (entry 7). These conditions afforded a 79% yield of the
desired product 13a.
Once we had discovered conditions that provided satisfactory
results for the coupling of 12a with bromobenzene we began to
explore the scope of the amide carboamination reactions. As
shown in Table 2, both aryl chlorides and aryl bromides could
be employed as coupling partners, and the reaction was
effective with electron-rich, electron-neutral, and electron-poor
electrophiles. The coupling of heteroaryl halides was also
accomplished, albeit in modest yields. Substrates 12c (R = H,
R1 = Me) and 12d (R = H, R1 = Ph) bearing a substituent at
the allylic position were transformed to trans-disubstituted
lactams 13d−j in good yield with good to excellent
diastereoselectivity. Not surprisingly, increasing the size of the
allylic group from methyl to phenyl led to increased
diastereoselectivities. In contrast, diastereoselectivities were
poor in reactions of 12b (R = Me, R1 = H) due to base-
mediated scrambling of the α-stereocenter in the lactam
products 13b−c.24 Unfortunately efforts to employ weaker
bases were unsuccessful. Although substitution on the back-
bone of the substrate was tolerated, efforts to transform
substrates bearing a substituent at the internal or terminal
alkene carbon atom failed to generate the desired products.
To further explore the scope of these transformations, we
elected to investigate the synthesis of six-membered lactams
from substituted hex-5-eneamide derivatives. As such, we
prepared substrate 14 and investigated its reactivity in the
Pd-catalyzed alkene carboamination reactions. Unfortunately,
despite extensive studies with a number of different catalyst
systems and reaction conditions, efforts to couple 14 with
bromobenzene provided little or none of the desired product
15 (Scheme 3).
Table 1. Optimization Studies
b
entry
[Pd]
ligand
base
yield
cd
,
1
2
3
4
5
6
7
Pd2(dba)3
PdCl2(MeCN)2
Pd(OAc)2
PdBr2
XPhos
CPhos
XPhos
XPhos
XPhos
RuPhos
XPhos
Cs2CO3
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
LiOtBu
<5%
34%
15%
69%
<5%
58%
79%
c
Pd(OAc)2
Pd(OAc)2
PdBr2
a
Conditions: 1 equiv of 12a, 2.0 equiv of PhBr, 2.0 equiv of base, 2.5
mol % Pd2(dba)3 or 5 mol % Pd(OAc)2 or 5 mol %PdBr2, 10 mol %
b
ligand, solvent (0.1 M), 100 °C, 4−16 h. Yields were determined by
c
1H NMR using phenanthrene as an internal standard. Yields reported
1
as <5% indicate the desired product was not observed by H NMR
d
analysis of the crude reaction mixture. The reaction was conducted in
1,4 dioxane solvent.
examined the conditions reported by Cacchi; however, these
conditions failed to produce the desired lactam product;
unreacted starting material was observed along with Heck
arylation of the alkene (entry 1). We subsequently varied the
palladium source, base, solvent, and phosphine ligand, to
a
Table 2. Pd-Catalyzed Synthesis of γ-Lactams
a
Conditions: 1 equiv of 12, 2.0 equiv of ArBr, 2.0 equiv of base, 4−10 mol % [Pd], 8−20 mol % ligand, solvent (0.1 M), 100 °C, 4−16 h. Yields are
b
isolated yields (average of two or more experiments). The reaction was conducted using an aryl chloride rather than an aryl bromide.
B
DOI: 10.1021/acs.joc.7b00041
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Having successfully prepared a range of PMP-protected
lactams, we sought to illustrate the feasibility of removing the
PMP protecting group. Fortunately this proved to be fairly
straightforward (Scheme 4), as treatment of product 13a with
cerium(IV) ammonium nitrate in acetonitrile/water led to
clean deprotection after 1 h, affording product 28 in 96%
isolated yield (76% overall yield from 12a over the two step
carboamination/deprotection sequence).
Scheme 3. Unsuccessful Pd-Catalyzed Carboamination of 14
Finally, we sought to obtain information about the
mechanism of the carboamination reaction and the key C−N
bond forming step, which in principle may occur via either syn-
or anti-aminopalladation of the alkene.25,26 As such, deuterated
4-pentenamide substrate 21 was synthesized and subjected to
our optimized reaction conditions (Scheme 5). This trans-
formation afforded deuterated lactam 22, which results from
anti-addition to the alkene, in 63% yield with >20:1 dr.27,28
The result of this stereochemical probe indicates the
products of these reactions are generated via anti-amino-
palladation of the alkene,25,26 rather than syn-aminopallada-
tion.29−33 As such, the mechanism of the amide-forming
reactions appears to be similar to related transformations of
other electron-deficient nitrogen nucleophiles such as sulfa-
mides26,34 and sulfonamides35 and likely proceeds as illustrated
in Scheme 6. The catalytic cycle is initiated by oxidative
addition of the aryl bromide to Pd(0) to afford 23.
Coordination of the alkene to the metal activates the alkene
for attack by the pendant amide nucleophile, and anti-
aminopalladation of resulting intermediate 24 ensues to provide
25. Finally, C−C bond-forming reductive elimination of 25
yields the lactam product and regenerates the Pd(0) catalyst.
We reasoned that the failure of substrate 14 to undergo the
desired transformation may be due to entropic factors
associated with generating the larger sized ring. It seemed
that substrates with less conformational flexibility would
therefore be more likely to undergo the Pd-catalyzed
carboamination, so our attention turned to substrates 16 and
17 derived from N-allylindole-2-carboxylic acid and the
analogous pyrrole derivative. As shown in Table 3, the
a
Table 3. Optimization Studies
b
b
entry
[Pd]
PdBr2
ligand
19a yield
20a yield
1
2
3
4
5
6
7
XPhos
XPhos
CPhos
RuPhos
BrettPhos
SPhos
10%
<5%
24%
60%
29%
87%
39%
c
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdBr2
<5%
c
<5%
CONCLUSION
17%
42%
■
In conclusion, we have explored and significantly expanded the
scope of Pd-catalyzed alkene carboamination reactions of amide
nucleophiles. These transformations afford substituted γ- and δ-
lactam derivatives in good yield with moderate diastereose-
lectivity. The reactions are effective with a range of different
aryl bromide electrophiles, and deuterium labeling studies
indicate the mechanism of C−N bond formation involves anti-
aminopalladation of the alkene.
c
<5%
d
d
Pd(OAc)2
SPhos
94%(98%)
91%(96%)
a
Conditions: 1 equiv of 16 or 17, 2.0 equiv of 4-bromobenzophenone,
2.0 equiv of base, 2 mol % [Pd], 8 mol % ligand, solvent (0.1 M), 100
b
°C, 4−16 h. Yields were determined by 1H NMR using phenanthrene
c
as an internal standard. Yields reported as <5% indicate the desired
1
product was not observed by H NMR analysis of the crude reaction
d
mixture. Isolated yield. The differences between NMR yields and
isolated yields reflect experimental error in the measurement of NMR
yields.
EXPERIMENTAL SECTION
■
General. All reactions were carried out under a nitrogen
atmosphere in flame- or oven-dried glassware. All reagents were
obtained from commercial sources and were used as obtained unless
otherwise noted. Palladium(II) bromide and palladium(II) acetate
were purchased from Strem Chemical Co. and used without further
purification. SPhos and XPhos were purchased from Sigma-Aldrich
Chemical Co. and used without further purification. Dichloromethane,
toluene, and tetrahydrofuran were purified using a GlassContour
solvent purification system. Pent-4-eneamide,19 N-methylpent-4-
eneamide,17 tert-butyl pent-4-enoyl carbamate,36 and (E)-tert-butyl-5-
d-pent-4-enylcarbamate37 were synthesized according to published
procedures. Benzotrifluoride was purified by distillation from CaH2
prior to use. Structural and stereochemical assignments were based on
2-D COSY and NOESY experiments. Ratios of diastereomers were
conditions that proved optimal for the generation of γ-lactams
provided unsatisfactory results in the coupling of 16 or 17 with
4-bromobenzophenone 18 (entry 1). However, use of
Pd(OAc)2 in place of PdBr2 led to improved results, and
after examining a few biarylphosphine derivatives we found that
the S-Phos ligand provided excellent results for the formation
of both 19a (94% NMR yield) and 20a (91% NMR yield).
Having successfully optimized conditions, we proceeded to
explore the coupling of 16 and 17 with a range of different aryl
bromides. As shown in Table 4, these reactions were effective
with electron-rich, electron-poor, o-substituted, and hetero-
aromatic electrophiles. The substituted lactam products were
generally formed in good to excellent yields under our standard
conditions, although use of tert-butanol as solvent provided
optimal results for the reaction of 16 with 2-brombenzo-
trifluoride to afford 19e, and toluene was superior to PhCF3 as
a solvent for the coupling of 17 with N,N-dimethyl-4-
bromoaniline to afford 20c.
1
determined by H NMR analysis. Yields refer to isolated yields of
1
compounds estimated to be ≥95% pure as determined by H NMR
analysis unless otherwise noted. The yields reported in the
Experimental Section describe the result of a single experiment,
whereas yields reported in Tables 2 and 4 and Schemes 4−5 are
averages of two or more experiments. Thus, the yields reported in the
Experimental Section may differ from those shown in Tables 2 and 4
and Schemes 4−5.
C
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a
Table 4. Pd-Catalyzed Synthesis of δ-Lactams
a
Conditions: 1 equiv of 16 or 17, 2.0 equiv of ArBr, 2.0 equiv of base, 2 mol % Pd(OAc)2, 6 mol % S-Phos, PhCF3 (0.2 M), 100 °C, 4−16 h. Yields
b
c
are isolated yields (average of two or more experiments). The reaction was conducted using tert-butyl alcohol as solvent. The reaction was
conducted using toluene as solvent.
separatory funnel. The mixture was extracted with ethyl acetate (3 ×
10 mL), and the combined organic layers were washed with 1 M HCl
(10 mL) and saturated aqueous NaHCO3 (10 mL), then were dried
over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
The crude product was then purified by flash chromatography on silica
gel using 30−40% ethyl acetate/hexanes as the eluent, unless
otherwise noted.
Scheme 4. Removal of PMP Protecting Group from 13a
N-(4-Methoxyphenyl)-pent-4-enamide (12a).38 The title com-
pound was prepared from 4-pentenoic acid (0.98 g, 9.7 mmol) and p-
anisidine (1.20 g, 9.7 mmol) according to General Procedure 1. This
procedure afforded 1.62 g (87%) of the title compound as a light
Scheme 5. Stereochemistry of Alkene Addition
brown solid, mp 91−92 °C (lit.38 mp 86−88 °C). H NMR (700
1
MHz, CDCl3) δ 7.39 (dd, J = 2.7, 9.7 Hz, 2 H), 7.07 (s, 1 H), 6.87−
6.82 (m, 2 H), 5.92−5.85 (m, 1 H), 5.19−5.09 (m, 2 H), 3.78 (s, 3 H),
2.51−2.45 (m, 2 H), 2.43 (dd, J = 6.3, 7.8 Hz, 2 H); 13C NMR (176
MHz, CDCl3) δ 170.2, 156.4, 136.9, 121.7, 115.9, 114.1, 55.5, 36.7,
29.5.
Scheme 6. Catalytic Cycle
N-(4-Methoxyphenyl)-2-methylpent-4-enamide (12b).38 The title
compound was prepared from 2-methyl 4-pentenoic acid (2.22 g, 19.4
mmol), and p-anisidine (2.40 g, 19.4 mmol) according to General
Procedure 1. This procedure afforded 2.06 g (95%) of the title
compound as a light brown solid, mp 82−83 °C (lit.38 mp 65−68 °C).
1H NMR (700 MHz, CDCl3) δ 7.42−7.35 (m, 2 H), 7.14 (s, br, 1 H),
6.86−6.82 (m, 2 H), 5.87−5.76 (m, 1 H), 5.16−5.09 (m, 2 H), 3.73
(s, 3 H), 2.53−2.43 (m, 1 H), 2.42−2.33 (m, 1 H), 2.22 (dt, J = 7.0,
14.1 Hz, 1 H), 1.23 (s, 3 H); 13C NMR (176 MHz, CDCl3) δ 173.8,
135.7, 130.9, 121.7, 117.2, 114.1, 55.5, 42.1, 38.5, 17.5.
N-(4-Methoxyphenyl)-3-methylpent-4-enamide (12c).38 The title
compound was prepared from 3-methyl-4-pentenoic acid (1.11 g, 9.7
mmol) and p-anisidine (1.20 g, 9.7 mmol) according to General
Procedure 1. This procedure afforded 0.87 g (78%) of the title
compound as a pale brown solid, mp 91−92 °C (lit.38 mp 57−60 °C).
1H NMR (700 MHz, CDCl3) δ 7.40−7.36 (m, 2 H), 7.05 (s, br, 1 H),
6.91−6.82 (m, 2 H), 5.88−5.80 (m, 1 H), 5.12−4.99 (m, 2 H), 3.77
(s, 3 H), 2.83−2.74 (m, 1 H), 2.38−2.33 (m, 1 H), 2.31−2.22 (m, 1
H), 1.11 (d, J = 6.7 Hz, 3 H); 13C NMR (176 MHz, CDCl3) δ 142.7,
121.8, 114.1, 113.9, 55.5, 44.6, 34.9, 19.7.
Experimental Procedures and Compound Characterization
Data for Substrates. General Procedure 1.2 A flame-dried flask
equipped with a stir bar was cooled under a stream of nitrogen and
charged with the appropriate carboxylic acid (1.0 equiv), 1,1′-
carbonyldiimidazole (1.0 equiv), and tetrahydrofuran (0.95 M). The
resulting mixture was stirred at rt for 2 h, then the appropriate aniline
(1.0 equiv) was added slowly, and the mixture was stirred at rt for 16
h. Water was then added, and the mixture was transferred to a
N-(4-Methoxyphenyl)-3-phenylpent-4-enamide (12d).17 The title
compound was prepared from 3-phenyl-4-pentenoic acid (1.71 g, 9.7
D
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1
mmol) and p-anisidine (1.20 g, 9.7 mmol) according to General
Procedure 1. This procedure afforded 0.95 g (35%) of the title
compound as a pale brown solid, mp 109−110 °C (lit.17 mp not
as a yellow solid, mp 117−118 °C. H NMR (400 MHz, CDCl3) δ
7.51 (s, 1 H), 7.48−7.39 (m, 2 H), 7.24 (s, 1 H), 6.93−6.79 (m, 3 H),
6.67 (dt, J = 1.8, 3.8 Hz, 1 H), 6.16 (dt, J = 2.1, 4.1 Hz, 1 H), 6.08−
5.93 (m, 1 H), 5.13 (dt, J = 1.6, 10.3 Hz, 1 H), 5.01 (ddq, J = 1.7, 5.3,
8.8 Hz, 2 H), 3.78 (d, J = 1.8 Hz, 3 H); 13C NMR (100 MHz, CDCl3)
δ 159.7, 156.3, 134.9, 131.0, 127.4, 125.3, 122.0, 116.5, 114.2, 112.1,
107.8, 77.2, 55.5, 51.0; IR (film) 3320, 1638 cm−1. HRMS (ESI+ TOF)
m/z: [M + H]+ calculated for C15H16N2O2 257.1285; found 257.1288.
Experimental Procedures and Compound Characterization
Data for Lactam Products. General Procedure 2: Synthesis of Five-
Membered Lactams. A flame-dried Schlenk tube equipped with a stir
bar was cooled under a stream of nitrogen and charged with the amide
substrate (1.0 equiv), the aryl halide (2.0 equiv), LiOtBu (2.0 equiv),
PdBr2 (4−10 mol %), and XPhos (8−20 mol %). The tube was purged
with nitrogen, and benzotrifluoride (5 mL/mmol substrate) was added
via syringe. The mixture was heated to 100 °C with stirring until the
reaction was complete as determined by TLC analysis. The reaction
mixture was cooled to room temperature, quenched with saturated
aqueous ammonium chloride (3 mL), and extracted with dichloro-
methane (3 × 2 mL). The collected organic layers were then dried
over anhydrous sodium sulfate, decanted, and concentrated in vacuo
and subsequently purified by flash chromatography on silica gel using
30−60% ethyl acetate/hexanes as the eluent unless otherwise noted.
( )-5-Benzyl-1-(4-methoxyphenyl)pyrrolidine-2-one (13a). The
title compound was prepared from substrate 12a (40 mg, 0.20
mmol), bromobenzene (42 μL, 0.40 mmol), LiOtBu (32 mg, 0.40
mmol), PdBr2 (1.5 mg, 0.006 mmol), and XPhos (8.4 mg, 0.018
mmol) according to General Procedure 2. This procedure afforded 39
mg (69%) of the title compound as a yellow oil. 1H NMR (700 MHz,
CDCl3) δ 7.37 (dd, J = 2.5, 9.0 Hz, 2 H), 7.28 (td, J = 2.3, 7.6 Hz, 2
H), 7.26−7.19 (m, 1 H), 7.10 (dd, J = 2.3, 7.8 Hz, 2 H), 7.00−6.92
(m, 2 H), 4.41−4.31 (m, 1 H), 3.82 (s, 3 H), 3.02−2.93 (m, 1 H),
2.64−2.55 (m, 1 H), 2.45−2.34 (m, 2 H), 2.17−2.05 (m, 1 H), 1.94−
1.84 (m, 1 H); 13C NMR (176 MHz, CDCl3) δ 136.9, 130.4, 129.2,
128.5, 126.7, 125.7, 114.5, 61.2, 55.5, 39.4, 30.8, 23.4; IR (film) 1682.8,
1506.4, 1239.7 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated
for C18H19NO2 282.1489; found 282.1488.
1
reported). H NMR (700 MHz, CDCl3) δ 7.32 (d, J = 7.6 Hz, 2 H),
7.28−7.18 (m, 5 H), 6.80 (d, 2 H), 6.11−5.99 (m, 1 H), 5.15−5.10
(m, 2 H), 3.95 (q, J = 7.3 Hz, 1 H), 3.76 (s, 3 H), 2.77 (dd, J = 7.2,
14.1 Hz, 1 H), 2.67 (dd, J = 7.8, 14.1 Hz, 1 H); 13C NMR (176 MHz,
CDCl3) δ 169.2, 140.2, 130.6, 128.8, 127.6, 126.9, 122.0, 115.2, 114.0,
55.4, 46.1, 43.8.
N-(4-Methoxyphenyl)hex-5-enamide (14).38 A flame-dried round-
bottom flask and stir bar was charged with 5-hexenoic acid (0.7 mL,
5.9 mmol), benzene (15 mL), and triethylamine (3 mL, 21.5 mmol).
Oxalyl chloride (0.8 mL, 9.3 mmol) was slowly added, and the reaction
was stirred overnight at rt (12 h). Neat p-anisidine (3.0 g, 24.4 mmol)
was then added, and the reaction mixture was stirred at rt for 2 h. The
reaction was slowly quenched through addition of water (10 mL). The
resulting mixture was extracted with ethyl acetate (3 × 50 mL), and
the organic layers were combined, dried over anhydrous sodium
sulfate, and concenterated in vacuo to afford 524 mg (41%) of the title
compound as an off-yellow solid, mp 69−71 °C (lit.38 mp 61−63 °C).
1H NMR (500 MHz, CDCl3) δ 7.47−7.38 (m, 2 H), 7.05 (s, 1 H),
6.93−6.91−6.82 (m, 2 H), 5.82 (ddt, J = 6.7, 10.2, 17.0 Hz, 1 H),
5.12−4.99 (m, 2 H), 3.80 (s, 3 H), 2.35 (t, J = 7.5 Hz, 2 H), 2.22−2.15
(m, 2 H), 1.85 (p, J = 7.4 Hz, 2 H).
1-Allyl-N-(4-methoxyphenyl)-1H-indole-2-carboxamide (16).39
Ethyl indole-2-carboxylate (1.91 g, 10.1 mmol) was dissolved in
N,N-dimethylformamide (10 mL), and the resulting solution was
added dropwise to a suspension of sodium hydride (470 mg, 11.8
mmol) in N,N-dimethylformamide (10 mL) at 0 °C. The mixture was
stirred for 30 min at rt, and then a solution of allyl bromide (1.3 mL,
15.0 mmol) was added dropwise. The mixture was stirred at 50 °C
overnight, then was cooled to rt, and poured into a mixture of ice and
water (20 mL). Diethyl ether (20 mL) was added, and the mixture was
transferred to a separatory funnel. The layers were separated, and the
aqueous layer was then extracted with diethyl ether (3 × 25 mL). The
combined organic layers were washed with water (5 × 25 mL) and
brine (25 mL), dried over MgSO4, filtered, and concentrated in vacuo
to afford a mixture of ethyl 1-allyl-indole-2-carboxylate and N,N-
dimethylformamide, which was not further purified. Ethanol (15 mL)
and 5 M sodium hydroxide (15 mL) were added to the mixture, which
was then heated to reflux overnight. The mixture was then cooled to rt,
ethanol was evaporated under reduced pressure, and the aqueous layer
was acidified with 5 M hydrochloric acid until pH 1 was achieved. The
resulting mixture was extracted with ethyl acetate (3 × 30 mL), and
the organic layers were dried over magnesium sulfate, filtered, and
concentrated in vacuo to afford 1-allyl-indole-2-carboxylic acid which
was used without further purification.
(
)-5-(4-Benzoylbenzyl)-1-(4-methoxyphenyl)-3-methyl-
pyrrolidin-2-one (13b). The title compound was prepared from
substrate 12b (35 mg, 0.16 mmol), 4-bromobenzophenone (110 mg,
0.42 mmol), LiOtBu (38 mg, 0.45 mmol), PdBr2 (1.9 mg, 0.007
mmol), and XPhos (8.8 mg, 0.018 mmol) according to General
Procedure 2. This procedure afforded 50 mg (79%) of the title
compound as a pale yellow foam. The compound was obtained as a
1:1 mixture of diastereomers as judged by 1H NMR analysis. Data are
1
for the mixture. H NMR (700 MHz, CDCl3) δ 7.78−7.68 (m, 4 H),
7.57 (dd, J = 5.3, 9.0 Hz, 2 H), 7.48 (d, J = 2.7 Hz, 2 H), 7.47 (s, 2 H),
7.48−7.41 (m, 2 H), 7.44−7.36 (m, 2 H), 7.27−7.13 (m, 8 H), 6.96−
6.91 (m, 4 H), 4.42−4.35 (m, 1 H), 4.30−4.24 (m, 1 H), 3.80 (s, 6 H),
3.15−3.10 (m, 1 H), 3.03−2.98 (m, 1 H), 2.76−2.69 (m, 1 H), 2.59−
2.52 (m, 1 H), 2.52−2.45 (m, 1 H), 2.42−2.30 (m, 1 H), 2.18−2.12
(m, 1 H), 1.87−1.76 (m, 3 H), 1.71 (s, 1 H), 1.47−1.41 (m, 1 H),
1.30−1.21 (m, 3 H), 1.24−1.17 (m, 3 H). 13C NMR (176 MHz,
CDCl3) δ 196.2, 176.9, 176.4, 157.3, 142.2, 142.0, 137.6, 136.0, 136.0,
132.4, 130.6, 130.4, 130.3, 129.9, 129.2, 129.1, 128.3, 126.4, 125.0,
114.4, 58.9, 58.7, 55.5, 40.8, 38.9, 36.8, 35.9, 33.9, 31.9, 25.9, 16.7,
16.2; IR (film) 1659.1, 1510.2, 1249.2 cm−1. HRMS (ESI+ TOF) m/z:
[M + H]+ calculated for C26H25NO3 400.1907; found 400.1917.
( )-5-[(1-Benzyl-1H-indol-5-yl)methyl]-1-(4-methoxyphenyl)-3-
methyl-pyrrolidin-2-one (13c). The title compound was prepared
from substrate 12b (43 mg, 0.20 mmol), N-benzyl-5-chloroindole
(122 mg, 0.50 mmol), LiOtBu (39 mg, 0.49 mmol), PdBr2 (1.9 mg,
0.007 mmol), and XPhos (8.8 mg, 0.018 mmol) according to General
Procedure 2. This procedure afforded 50 mg (43%) of the title
compound as an orange oil. The compound was obtained as a 1:1
1,1′-Carbonyldiimidazole (1.65 g, 10.1 mmol) was added to a
solution of 1-allyl-indole-2-carboxylic acid in tetrahydrofuran (20 mL),
and the resulting mixture was stirred at rt for 2 h. Neat p-anisidine
(1.42 g, 11.5 mmol) was added, and the resulting mixture was stirred
at rt overnight. The mixture was then transferred to a separatory
funnel and washed with saturated aqueous NaHCO3 (20 mL), ethyl
acetate (3 × 25 mL), and brine (20 mL). The combined organic layers
were dried over magnesium sulfate, filtered, and concentrated in vacuo
to afford the title compound (2.02 g, 66% yield over three steps) as a
white solid, mp 177−178 °C (lit.39 mp not reported). H NMR (500
1
MHz, CDCl3) δ 7.88 (s, 1 H), 7.68 (d, J = 8.0 Hz, 1 H), 7.59−7.49
(m, 2 H), 7.41 (d, J = 8.4 Hz, 1 H), 7.35 (ddd, J = 1.2, 6.9, 8.2 Hz, 1
H), 7.25−7.13 (m, 1 H), 7.02 (s, 1 H), 6.95−6.89 (m, 2 H), 6.06 (ddt,
J = 5.1, 10.2, 17.0 Hz, 1 H), 5.24 (dt, J = 1.8, 5.2 Hz, 2 H), 5.13 (dq, J
= 1.6, 10.3 Hz, 1 H), 4.98 (dq, J = 1.6, 17.1 Hz, 1H), 3.83 (s, 3 H); 13C
NMR (126 MHz, CDCl3) δ 160.3, 156.6, 138.7, 134.1, 131.7, 130.7,
126.2, 124.4, 122.0, 120.8, 116.2, 114.3, 114.2, 110.7, 104.6, 55.5, 46.9,
14.6.
1
mixture of diastereomers as judged by H NMR analysis. Data are for
1-Allyl-N-(4-methoxyphenyl)-1H-pyrrole-2-carboxamide (17).
The title compound was prepared using a procedure analogous to
that employed for the preparation of 16 except methyl pyrrole-2-
carboxylate (1.40 g, 10.1 mmol) was used as the starting material. This
procedure afforded the title compound (1.92 g, 75% over three steps)
the mixture. 1H NMR (700 MHz, CDCl3) δ 7.51−7.47 (m, 2 H), 7.37
(dd, J = 1.6, 18.0 Hz, 2 H), 7.34−7.23 (m, 8 H), 7.18 (dd, J = 5.1, 8.4
Hz, 2 H), 7.13−7.05 (m, 6 H), 6.99−6.93 (m, 4 H), 6.89 (ddd, J = 1.6,
8.3, 10.8 Hz, 2 H), 6.52 (s, 2 H), 5.29 (s, 4 H), 4.38−4.30 (m, 1 H),
E
DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
4.26−4.19 (m, 1 H), 3.82 (d, J = 2.4 Hz, 6 H), 3.19 (dd, J = 3.7, 13.5
Hz, 1 H), 3.03 (dd, J = 3.4, 13.7 Hz, 1 H), 2.67 (dd, J = 9.3, 13.7 Hz, 1
H), 2.55−2.43 (m, 3 H), 2.32−2.19 (m, 2 H), 1.76−1.68 (m, 1 H),
1.54−1.47 (m, 1 H), 1.33−1.21 (m, 3 H), 1.16 (d, J = 7.2 Hz, 3 H);
13C NMR (176 MHz, CDCl3) δ 137.4, 135.3, 128.8, 128.75, 128.69,
127.6, 126.79, 126.77, 126.3, 124.8, 123.1, 121.3, 121.2, 114.4, 114.3,
109.7, 109.6, 101.3, 59.7, 59.6, 55.5, 50.2, 40.8, 38.6, 35.9, 34.0, 31.8,
16.7, 16.3; IR (film) 1688.4, 1509.1, 1244.9, 1178.5 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calculated for C28H28N2O2 425.2224;
found 425.2234.
This procedure afforded 51 mg (75%) of the title compound as a
yellow oil. The compound was obtained as a >20:1 mixture of
1
diastereomers as judged by H NMR analysis. Data are for the major
isomer. 1H NMR (700 MHz, CDCl3) δ 7.38 (dd, J = 2.5, 9.1 Hz, 2 H),
7.32−7.24 (m, 2 H), 7.24−7.19 (m, 1 H), 7.08 (dd, J = 2.2, 7.9 Hz, 2
H), 7.03−6.94 (m, 4 H), 6.80 (dd, J = 2.4, 8.7 Hz, 2 H), 4.37−4.31
(m, 1 H), 3.82 (s, 3 H), 3.78 (s, 3 H), 3.32−3.27 (m, 1 H), 2.94−2.88
(m, 1 H), 2.83−2.76 (m, 2 H), 2.58−2.51 (m, 1 H); 13C NMR (176
MHz, CDCl3) δ 157.5, 130.5, 128.9, 126.9, 126.6, 125.3, 114.4, 114.0,
69.1, 55.5, 55.2, 40.5, 38.9, 37.4; IR (film) 1688.0, 1510.4, 1246.8,
1032.2 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for
C25H25NO3 388.1907; found 388.1905.
( )-(4S*,5R*)-5-(4-Methoxybenzyl)-1-(4-methoxyphenyl)-4-
methylpyrrolidin-2-one (13d). The title compound was prepared
from substrate 12c (54 mg, 0.25 mmol), 4-bromoanisole (60 μL, 0.48
mmol), LiOtBu (31 mg, 0.39 mmol), PdBr2 (2.4 mg, 0.009 mmol),
and XPhos (14.2 mg, 0.029 mmol) according to General Procedure 2.
This procedure afforded 52 mg (66%) of the title compound as an
orange oil. The compound was obtained as a 9:1 mixture of
diastereomers as judged by 1H NMR analysis. Data are for the
( )-(4R*,5R*)-5-(4-Methoxybenzyl)-1-(4-methoxyphenyl)-4-
phenylpyrrolidin-2-one (13h). The title compound was prepared
from substrate 12d (54 mg, 0.19 mmol), bromobenzene (42 μL, 0.40
mmol), LiOtBu (38 mg, 0.47 mmol), PdBr2 (2.1 mg, 0.078 mmol),
and XPhos (13.5 mg, 0.028 mmol) according to General Procedure 2.
This procedure afforded 48 mg (65%) of the title compound as a
yellow oil. The compound was obtained as a >20:1 mixture of
1
major isomer. H NMR (700 MHz, CDCl3) δ 7.36 (dd, J = 2.7, 9.5
1
diastereomers as judged by H NMR analysis. Data are for the major
Hz, 2 H), 7.02−6.92 (m, 4 H), 6.86−6.77 (m, 2 H), 3.88 (dt, J = 3.6,
7.8 Hz, 1 H), 3.83−3.72 (m, 6 H), 2.86 (dd, J = 3.7, 13.9 Hz, 1 H),
2.64−2.56 (m, 1 H), 2.53 (dd, J = 8.6, 17.0 Hz, 1 H), 2.23 (t, J = 9.3
Hz, 1 H), 2.07−2.01 (m, 1 H), 1.01 (t, J = 5.2 Hz, 3 H); 13C NMR
(176 MHz, CDCl3) δ 173.5, 158.4, 157.4, 130.6, 130.2, 129.8, 128.8,
126.3, 125.5, 114.4, 114.3, 113.9, 113.8, 68.7, 64.4, 55.5, 55.2, 39.7,
39.2, 37.7, 37.7, 33.5, 30.2, 29.7, 20.7, 15.1; IR (film) 1681.4, 1509.3,
1242.3, 1177.1 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated
for C20H23NO3 326.1751; found 326.1748.
1
isomer. H NMR (700 MHz, CDCl3) δ 7.46−7.36 (m, 2 H), 7.29−
7.25 (m, 4 H), 7.27−7.15 (m, 2 H), 7.09−7.02 (m, 4 H), 6.99−6.93
(m, 2 H), 4.40−4.33 (m, 1 H), 3.82 (s, 3 H), 3.33−3.26 (m, 1 H),
3.01−2.96 (m, 1 H), 2.87−2.80 (m, 2 H), 2.56 (dd, J = 6.9, 17.4 Hz, 1
H); 13C NMR (176 MHz, CDCl3) δ 172.9, 157.8, 141.5, 136.0, 132.4,
130.3, 130.1, 130.0, 129.3, 129.0, 128.5, 127.1, 126.6, 125.7, 114.5,
68.6, 55.5, 41.5, 39.2, 39.0; IR (film) 1684.2, 1509.8, 1246.3, 1176.0
cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for C24H23NO2
358.1802; found 358.1801.
( )-(4S*,5R*)-5-(4-Benzoylbenzyl)-1-(4-methoxyphenyl)-4-
methylpyrrolidin-2-one (13e). The title compound was prepared
from substrate 12c (54 mg, 0.25 mmol), 4-bromobenzophenone (113
mg, 0.43 mmol), LiOtBu (36 mg, 0.45 mmol), PdBr2 (5.2 mg, 0.02
mmol), and XPhos (12.4 mg, 0.026 mmol) according to General
Procedure 2. This procedure afforded 59 mg (60%) of the title
compound as a yellow oil. The compound was obtained as an 8:1
( )-(4R*,5R*)-1-(4-Methoxyphenyl)-4-phenyl-5-(thiophen-2-
ylmethyl)pyrrolidin-2-one (13i). The title compound was prepared
from substrate 12d (41 mg, 0.15 mmol), 2-bromothiophene (30 μL,
0.31 mmol), LiOtBu (31 mg, 0.39 mmol), PdBr2 (3.9 mg, 0.015
mmol), and XPhos (15.2 mg, 0.032 mmol) according to General
Procedure 2. This procedure afforded 35 mg (49%) of the title
compound as a pale yellow oil. The compound was obtained as a
1
mixture of diastereomers as judged by H NMR analysis. Data are for
1
the major isomer. 1H NMR (700 MHz, CDCl3) δ 7.77−7.68 (m, 4 H),
7.63−7.54 (m, 1 H), 7.49−7.43 (m, 2 H), 7.35−7.29 (m, 2 H), 7.20−
7.14 (m, 2 H), 6.96−6.90 (m, 2 H), 4.00−3.97 (m, 1 H), 3.79 (s, 3 H),
3.00 (dd, J = 4.2, 13.8 Hz, 1 H), 2.78 (dd, J = 8.0, 13.8 Hz, 1 H), 2.71−
2.59 (m, 1 H), 2.31−2.21 (m, 1 H), 2.10 (dd, J = 4.9, 17.1 Hz, 1 H),
1.05 (d, J = 6.9 Hz, 3 H); 13C NMR (176 MHz, CDCl3) δ 196.2,
173.4, 157.7, 142.1, 137.6, 136.0, 132.4, 130.3, 130.2, 129.9, 129.2,
128.8, 128.3, 126.4, 125.7, 114.5, 114.2, 68.4, 64.3, 55.5, 39.0, 38.9,
30.6, 20.5; IR (film) 1675.6, 1510.7, 1249.0, 909.6 cm−1. HRMS (ESI+
TOF) m/z: [M + H]+ calculated for C26H25NO3 422.1727; found
422.1739.
>20:1 mixture of diastereomers as judged by H NMR analysis. Data
1
are for the major isomer. H NMR (400 MHz, CDCl3) δ 7.47−7.34
(m, 2H), 7.36−7.21 (m, 3H), 7.25−7.14 (m, 3H), 6.99−6.89 (m, 3H),
6.76 (dd, J = 3.6, 1.2 Hz, 1H), 4.40−4.31 (m, 1H), 3.81 (s, 3H), 3.36
(dt, J = 4.5, 9.1 Hz, 1H), 3.11 (d, J = 5.1 Hz, 2H), 2.80 (dd, J = 9.4,
17.5 Hz, 1H), 2.57 (dd, J = 5.0, 17.5 Hz, 1H); 13C NMR (176 MHz,
CDCl3) δ 173.2, 143.6, 137.6, 130.0, 129.0, 127.1, 127.0, 126.9, 126.7,
125.5, 124.8, 114.5, 68.4, 55.5, 40.6, 39.1, 32.0; IR (film) 2926.4,
1690.7, 1510.4, 1248.9 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calculated for C22H21NO2S 364.1368; found 364.1368.
( )-(4R*,5R*)-5-(2-Methoxybenzyl)-1-(4-methoxyphenyl)-4-
phenylpyrrolidin-2-one (13j). The title compound was prepared from
substrate 12d (42 mg, 0.15 mmol), 2-chloroanisole (45 μL, 0.35
mmol), LiOtBu (42 mg, 0.52 mmol), PdBr2 (3.5 mg, 0.013 mmol),
and XPhos (15.1 mg, 0.031 mmol) according to General Procedure 2.
This procedure afforded 48 mg (81%) of the title compound as a
yellow oil. The compound was obtained as a >20:1 mixture of
(
)-(2R*,3S*)-3-{[1-(4-Methoxyphenyl)-3-methyl-5-oxo-
pyrrolidin-2-yl]methyl}benzonitrile (13f). The title compound was
prepared from substrate 12c (41 mg, 0.19 mmol), 3-bromobenzoni-
trile (70 mg, 0.39 mmol), LiOtBu (42 mg, 0.52 mmol), PdBr2 (4.2 mg,
0.016 mmol), and XPhos (15.1 mg, 0.032 mmol) according to General
Procedure 2. This procedure afforded 35 mg (52%) of the title
compound as a colorless oil. The compound was obtained as a 9:1
1
diastereomers as judged by H NMR analysis. Data are for the major
isomer. 1H NMR (700 MHz, CDCl3) δ 7.46 (dd, J = 2.4, 9.3 Hz, 2 H),
7.22−7.12 (m, 4 H), 7.03 (dd, J = 1.7, 7.4 Hz, 1 H), 6.99−6.94 (m, 2
H), 6.96−6.90 (m, 2 H), 6.87−6.83 (m, 1 H), 6.74 (dd, J = 1.0, 8.2
Hz, 1 H), 4.48−4.41 (m, 1 H), 3.81 (s, 3 H), 3.69 (s, 3 H), 3.36−3.28
(m, 1 H), 3.21 (dd, J = 4.1, 13.4 Hz, 1 H), 3.05 (dd, J = 9.3, 17.4 Hz, 1
H), 2.67 (dd, J = 9.4, 13.4 Hz, 1 H), 2.60 (dd, J = 3.9, 17.4 Hz, 1 H);
13C NMR (176 MHz, CDCl3) δ 173.1, 157.5, 157.3, 144.4, 131.1,
130.7, 128.7, 128.2, 126.59, 126.56, 126.5, 125.3, 125.0, 120.5, 114.2,
110.3, 67.7, 55.5, 55.1, 40.8, 39.0, 34.5; IR (film) 1680.2, 1601.1,
1492.4, 1242.8 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated
for C25H25NO3 388.1907; found 388.1910.
1
mixture of diastereomers as judged by H NMR analysis. Data are for
the major isomer. 1H NMR (700 MHz, CDCl3) δ 7.51−7.47 (m, 1 H),
7.41−7.32 (m, 1 H), 7.31−7.24 (m, 4 H), 6.92 (dd, J = 2.7, 9.5 Hz, 2
H), 3.96−3.91 (m, 1 H), 3.80 (s, 3 H), 2.93 (dd, J = 4.3, 14.0 Hz, 1
H), 2.76 (dd, J = 7.7, 14.0 Hz, 1 H), 2.69−2.56 (m, 1 H), 2.23−2.18
(m, 1 H), 2.18−2.07 (m, 2 H), 1.09−1.05 (m, 3 H); 13C NMR (176
MHz, CDCl3) δ 168.2, 138.5, 133.7, 132.8, 131.0, 130.4, 130.1, 129.3,
125.8, 121.9, 118.5, 114.5, 114.1, 112.6, 68.2, 55.49, 55.45, 38.9, 38.5,
30.7, 24.3, 20.3; IR (film) 2226.8, 1682.0, 1509.8, 1244.7 cm−1. HRMS
(ESI+ TOF) m/z: [M + H]+ calculated for C20H20N2O2 321.1598;
found 321.1595.
General Procedure 3: Synthesis of Six-Membered Lactams. A
flame-dried Schlenk tube equipped with a stir bar was cooled under a
stream of nitrogen and charged with the amide substrate (1.0 equiv),
the aryl halide (2.0 equiv), LiOtBu (2.0 equiv), Pd(OAc)2 (2 mol %),
and SPhos (6 mol %). The tube was purged with nitrogen, and
( )-(4R*,5R*)-5-(4-Methoxyphenyl)-1-(4-methoxyphenyl)-4-
phenylpyrrolidin-2-one (13g). The title compound was prepared
from substrate 12d (54 mg, 0.19 mmol), 4-bromoanisole (50 μL, 0.40
mmol), LiOtBu (35 mg, 0.43 mmol), PdBr2 (4.1 mg, 0.015 mmol),
and XPhos (13.5 mg, 0.028 mmol) according to General Procedure 2.
F
DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
benzotrifluoride (5 mL/mmol substrate) was added via syringe. The
mixture was heated to 100 °C with stirring until the reaction was
complete as determined by TLC analysis. The reaction mixture was
cooled to room temperature, quenched with saturated aqueous
ammonium chloride (3 mL), and extracted with dichloromethane (3
× 2 mL). The collected organic layers were then dried over anhydrous
sodium sulfate, decanted, and concentrated in vacuo and subsequently
purified by flash chromatography on silica gel using 30−60% ethyl
acetate/hexanes as the eluent unless otherwise noted.
( )-3-(4-Benzoylbenzyl)-2-(4-methoxyphenyl)-3,4-dihydro-
pyrazino[1,2-a]indol-1(2H)-one (19a). The title compound was
prepared from substrate 16 (61 mg, 0.20 mmol), 4-bromobenzophe-
none (109 mg, 0.42 mmol), LiOtBu (35 mg, 0.44 mmol), Pd(OAc)2
(1.0 mg, 0.004 mmol), and SPhos (5.1 mg, 0.012 mmol) according to
General Procedure 3. This procedure afforded 95 mg (98%) of the
title compound as a viscous yellow oil. 1H NMR (500 MHz, CDCl3) δ
7.82−7.75 (m, 3 H), 7.69 (d, J = 8.0 Hz, 2 H), 7.64−7.55 (m, 1H),
7.49 (t, J = 7.7 Hz, 2 H), 7.42−7.30 (m, 4 H), 7.21 (d, J = 7.9 Hz, 2
H), 7.04 (d, J = 7.9 Hz, 2 H), 7.02−6.95 (m, 2 H), 4.34−4.28 (m, 1
H), 4.23 (qd, J = 2.9, 12.7 Hz, 2 H), 3.83 (s, 3 H), 3.20 (dd, J = 4.5,
13.4 Hz, 1 H), 2.83 (dd, J = 10.5, 13.4 Hz, 1 H); 13C NMR (100 MHz,
CDCl3) δ 196.1, 158.8, 158.6, 141.5, 137.4, 136.7, 136.4, 133.5, 132.5,
130.6, 130.0, 129.3, 128.9, 128.6, 128.3, 127.6, 124.9, 122.8, 120.9,
114.6, 109.5, 107.0, 62.0, 55.5, 41.9, 37.5; IR (film) 1648.5, 1605.3
cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for C32H26N2O3
487.2016; found 487.2018.
Hz, 3 H), 3.56 (t, J = 3.1 Hz, 1 H), 3.02−2.96 (m, 1 H), 2.55 (s, 1 H);
13C NMR (176 MHz, CDCl3) δ 158.8, 158.5, 140.3, 139.9, 136.7,
135.7, 133.5, 129.7, 129.6, 129.0, 128.73, 128.70, 128.50, 128.47,
127.50, 127.47, 127.37, 127.35, 127.31, 127.28, 126.85, 126.82, 124.71,
124.68, 122.68, 122.65, 120.7, 114.53, 114.51, 109.5, 106.84, 106.82,
77.2, 77.0, 76.8, 62.4, 62.3, 55.39, 55.36, 41.6, 36.9; IR (film) 1648
cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for C31H26N2O2
459.2067; found 459.2068.
2-(4-Methoxyphenyl)-3-(2-(trifluoromethyl)benzyl)-3,4-dihydro-
pyrazino[1,2-a]indol-1(2H)-one (19e). The title compound was
prepared from substrate 16 (61 mg, 0.20 mmol), 2-bromobenzo-
trifluoride (60 μL, 0.44 mmol), LiOtBu (34 mg, 0.42 mmol),
Pd(OAc)2 (1.1 mg, 0.005 mmol), and SPhos (5.7 mg, 0.014 mmol)
according to General Procedure 3, using tert-butyl alcohol as the
solvent instead of benzotrifluoride. This procedure afforded 76 mg
1
(85%) of the title compound as a yellow solid, mp 181−183 °C. H
NMR (500 MHz, CDCl3) δ 7.79 (d, J = 8.0 Hz, 1 H), 7.61 (d, J = 7.8
Hz, 1 H), 7.48−7.34 (m, 4 H), 7.28−7.20 (m, 3 H), 7.01−6.92 (m, 2
H), 6.89 (d, J = 7.6 Hz, 1 H), 4.40 (dt, J = 10.1, 4.3 Hz, 1 H), 4.33−
4.20 (m, 2 H), 3.84 (s, 3 H), 3.43 (dd, J = 4.7, 14.0 Hz, 1 H), 2.91 (dd,
J = 10.7, 13.8 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ 158.8, 158.5,
136.7, 135.0, 133.3, 133.2, 132.1, 129.2, 129.1, 129.1 (q, J = 13.9 Hz),
128.5, 127.7, 127.5, 126.6 (q, J = 6.3 Hz), 124.9, 124.1 (q, J = 273 Hz),
123.0, 122.9, 120.8, 114.5, 109.5, 107.2, 61.2, 55.5, 41.9, 34.7; IR (film)
1651 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for
C26H21F3N2O2 451.1628; found 451.1637.
( )-3-(4-Methoxybenzyl)-2-(4-methoxyphenyl)-3,4-dihydro-
pyrazino[1,2-a]indol-1(2H)-one (19b). The title compound was
prepared from substrate 16 (61 mg, 0.20 mmol), 4-bromoanisole
(50 μL, 0.40 mmol), LiOtBu (37 mg, 0.46 mmol), Pd(OAc)2 (1.0 mg,
0.004 mmol), and SPhos (5.2 mg, 0.013 mmol) according to General
Procedure 3. This procedure afforded 71 mg (90%) of the title
( )-3-(Benzo[d][1,3]dioxol-5-ylmethyl)-2-(4-methoxyphenyl)-3,4-
dihydropyrazino[1,2-a]indol-1(2H)-one (19f). The title compound
was prepared from substrate 16 (62 mg, 0.20 mmol), 5-bromobenzo-
[d][1,3]dioxole (80 μL, 0.66 mmol), LiOtBu (37 mg, 0.46 mmol),
Pd(OAc)2 (1.0 mg, 0.004 mmol), and SPhos (5.2 mg, 0.013 mmol)
according to General Procedure 3. This procedure afforded 80 mg
1
1
compound as a yellow solid, mp 140−142 °C. H NMR (700 MHz,
(92%) of the title compound as a yellow solid, mp 145−146 °C. H
CDCl3) δ 7.77 (d, J = 8.0 Hz, 1 H), 7.41−7.31 (m, 4 H), 7.25−7.17
(m, 2 H), 7.03−6.97 (m, 2 H), 6.86−6.77 (m, 4 H), 4.27 (s, 1 H),
4.22−4.12 (m, 2 H), 3.86 (s, 3 H), 3.79 (s, 3 H), 3.11 (dd, J = 4.1, 13.4
Hz, 1 H), 2.64 (dd, J = 10.9, 13.6 Hz, 1 H); 13C NMR (176 MHz,
CDCl3) δ 158.9, 158.7, 158.5, 136.8, 133.7, 130.3, 129.1, 128.8, 128.6,
127.6, 124.7, 122.8, 120.7, 114.6, 114.2, 109.5, 106.9, 62.7, 55.5, 55.3,
41.5, 36.4; IR (film) 1649 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calculated for C26H24N2O3 413.1860; found 413.1862.
NMR (700 MHz, CDCl3) δ 7.76 (d, J = 8.0 Hz, 1 H), 7.43−7.29 (m, 4
H), 7.29−7.16 (m, 2 H), 6.99 (d, J = 8.3 Hz, 2 H), 6.69 (d, J = 7.7 Hz,
1 H), 6.40 (d, J = 1.7 Hz, 1 H), 6.34 (dd, J = 1.8, 7.8 Hz, 1 H), 5.92
(dt, J = 1.3, 9.8 Hz, 2 H), 4.29 (d, J = 12.2 Hz, 1 H), 4.23−4.11 (m, 2
H), 3.90−3.80 (m, 3 H), 3.06 (dd, J = 4.1, 13.6 Hz, 1 H), 2.61 (dd, J =
10.8, 13.6 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ 158.9, 158.6,
148.0, 146.7, 136.8, 133.6, 130.4, 129.1, 128.6, 127.6, 124.8, 122.8,
122.5, 120.8, 114.6, 109.5, 109.3, 108.5, 107.0, 101.1, 62.6, 55.5, 41.6,
37.0; IR (film) 1652 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calculated for C26H22N2O4 427.1652; found 427.1656.
( )-2-(4-Methoxyphenyl)-3-[3-(trifluoromethyl)benzyl]-3,4-
dihydropyrazino[1,2-a]indol-1(2H)-one (19c). The title compound
was prepared from substrate 16 (72 mg, 0.24 mmol), 3-bromobenzo-
trifluoride (60 μL, 0.43 mmol), LiOtBu (35 mg, 0.44 mmol),
Pd(OAc)2 (1.1 mg, 0.005 mmol), and SPhos (5.7 mg, 0.014 mmol)
according to General Procedure 3. This procedure afforded 95 mg
( )-3-(4-Benzoylbenzyl)-2-(4-methoxyphenyl)-3,4-dihydro-
pyrrolo[1,2-a]pyrazin-1(2H)-one (20a). The title compound was
prepared from substrate 17 (68 mg, 0.27 mmol), 4-bromobenzo-
phenone (133 mg, 0.51 mmol), LiOtBu (41 mg, 0.52 mmol),
Pd(OAc)2 (1.5 mg, 0.006 mmol), and SPhos (6.0 mg, 0.014 mmol)
according to General Procedure 3. This procedure afforded 113 mg
1
(95%) of the title compound as a brown solid, mp 164−165 °C. H
NMR (500 MHz, CDCl3) δ 7.77 (d, J = 8.0 Hz, 1 H), 7.51 (d, J = 7.8
Hz, 1 H), 7.42−7.34 (m, 3 H), 7.34−7.29 (m, 2 H), 7.24−7.14 (m, 3
H), 7.09 (d, J = 7.7 Hz, 1 H), 7.02−6.92 (m, 2 H), 4.24 (ddd, J = 2.5,
5.0, 10.5 Hz, 1 H), 4.19 (d, J = 2.8 Hz, 2 H), 3.83 (d, J = 1.9 Hz, 3 H),
3.19 (dd, J = 4.5, 13.6 Hz, 1 H), 2.79 (dd, J = 10.6, 13.5 Hz, 1 H); 13C
NMR (126 MHz, CDCl3) δ 158.8, 158.6, 137.7, 136.7, 133.4, 132.8,
131.3 (q, J = 31.5 Hz), 129.4, 128.9, 128.6, 127.6, 126.0, 125.9 (q, 3.78
Hz), 125.0, 124.9, 124.0 (q, J = 3.8 Hz), 123.9 (q, J = 272 Hz), 122.8,
120.9, 114.7, 114.0, 109.4, 107.2, 62.1, 55.5, 41.7, 37.2, 29.7; IR (film)
1649 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for
C26H21F3N2O2 451.1628; found 451.1631.
1
(96%) of the title compound as a viscous yellow oil. H NMR (500
MHz, CDCl3) δ 7.83−7.63 (m, 4 H), 7.63−7.50 (m, 1 H), 7.50−7.40
(m, 2 H), 7.34−7.23 (m, 2 H), 7.14−7.06 (m, 2 H), 7.06−7.00 (m, 1
H), 6.98−6.91 (m, 2 H), 6.76−6.67 (m, 1 H), 6.29 (p, J = 2.3 Hz, 1
H), 4.29 (dd, J = 4.0, 12.9 Hz, 1 H), 4.16 (dt, J = 4.0, 9.1 Hz, 1 H),
3.92 (d, J = 12.8 Hz, 1 H), 3.82 (d, J = 2.1 Hz, 3 H), 3.24−3.13 (m, 1
H), 2.89−2.74 (m, 1 H); 13C NMR (126 MHz, CDCl3) δ 196.1,
158.4, 158.2, 141.7, 137.4, 136.4, 133.7, 132.5, 130.6, 129.9, 129.1,
128.7, 128.3, 124.4, 123.2, 114.5, 114.4, 110.3, 61.6, 55.5, 45.5, 37.2,
28.4, 14.1; IR (film) 1646 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calculated for C28H24N2O3 437.1860; found 437.1859.
( )-3-([1,1′-Biphenyl]-4-ylmethyl)-2-(4-methoxyphenyl)-3,4-
dihydropyrazino[1,2-a]indol-1(2H)-one (19d). The title compound
was prepared from substrate 16 (66 mg, 0.22 mmol), 4-bromobiphenyl
(95 mg, 0.41 mmol), LiOtBu (34 mg, 0.42 mmol), Pd(OAc)2 (1.1 mg,
0.005 mmol), and SPhos (6.0 mg, 0.015 mmol) according to General
Procedure 3. This procedure afforded 84 mg (86%) of the title
( )-4-{[2-(4-methoxyphenyl)-1-oxo-1,2,3,4-tetrahydropyrrolo-
[1,2-a]pyrazin-3-yl]methyl}benzo-nitrile (20b). The title compound
was prepared from substrate 17 (50 mg, 0.20 mmol), 4-bromo-
benzonitrile (72 mg, 0.40 mmol), LiOtBu (32 mg, 0.40 mmol),
Pd(OAc)2 (1.3 mg, 0.006 mmol), and SPhos (5.7 mg, 0.014 mmol)
according to General Procedure 3. This procedure afforded 65 mg
1
compound as an off-yellow solid, mp 176−178 °C. H NMR (700
1
MHz, CDCl3) δ 7.59 (d, J = 7.9 Hz, 1 H), 7.39 (d, J = 7.6 Hz, 2 H),
7.31 (d, J = 7.7 Hz, 2 H), 7.28−7.22 (m, 3 H), 7.21−7.14 (m, 4 H),
7.07−7.00 (m, 3 H), 6.83−6.77 (m, 4 H), 4.10 (d, J = 12.4 Hz, 1 H),
4.07−4.02 (m, 1 H), 3.97 (dd, J = 3.3, 12.3 Hz, 1 H), 3.65 (d, J = 2.3
(94%) of the title compound as a yellow solid, mp 174−176 °C. H
NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.9 Hz, 2 H), 7.20 (s, 1 H),
7.06 (d, J = 7.9 Hz, 2 H), 6.99−6.93 (m, 1 H), 6.88 (d, J = 8.6 Hz, 2
H), 6.68 (t, J = 2.0 Hz, 1 H), 6.29−6.22 (m, 1 H), 4.24 (dd, J = 4.1,
G
DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
13.0 Hz, 1 H), 4.12 (dd, J = 4.9, 10.1 Hz, 1 H), 3.82 (dd, J = 1.7, 12.9
Hz, 1 H), 3.78 (s, 3 H), 3.09 (dd, J = 4.8, 13.6 Hz, 1 H), 2.75 (dd, J =
10.4, 13.5 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 158.4, 158.1,
142.4, 133.5, 132.5, 130.0, 128.6, 124.2, 123.2, 118.5, 114.5, 114.4,
111.0, 110.3, 77.4, 61.3, 55.5, 45.6, 37.3; IR (film) 2227.3, 1641 cm−1.
HRMS (ESI+ TOF) m/z: [M + H]+ calculated for C22H19N3O2
358.1550; found 358.1555.
158.4, 158.2, 138.7, 133.7, 130.0, 128.6, 127.3, 126.7, 124.7, 124.3,
123.4, 117.9, 114.6, 114.55, 114.4, 112.1, 110.6, 110.1, 105.8, 61.8,
55.5, 55.48, 45.4, 31.0, 18.2; IR (film) 1640 cm−1. HRMS (ESI+ TOF)
m/z: [M + H]+ calculated for C19H18N2O2S 339.1162; found
339.1165.
Deprotection of the N-PMP Group From Product 13a. ( )-5-
Benzylpyrrolidin-2-one (28). A scintillation vial equipped with a stir
bar was charged with 13a (25 mg, 0.089 mmol), ammonium
cerium(IV) nitrate (320 mg, 0.58 mmol), acetonitrile (1.75 mL),
and water (0.35 mL). The resulting mixture was stirred at rt until the
starting material had been completely consumed as judged by TLC
analysis (ca. 1.5 h). Water (5 mL) was added, and the resulting
mixture was transferred to a separatory funnel and extracted with ethyl
acetate (3 × 5 mL). The organic layers were combined, dried over
sodium sulfate, and concentrated. The crude product was then purified
by flash chromatography on silica gel using 40−60% ethyl acetate/
hexanes as the eluent to afford 15 mg (96%) of the title compound as a
pale yellow oil. 1H NMR (700 MHz, CDCl3) δ 7.38 (s, 2 H), 7.33 (t, J
= 7.3 Hz, 1 H), 7.20 (s, 2 H), 6.73 (s, 1 H), 4.03 (s, 1 H), 2.88 (dd, J =
5.3, 13.7 Hz, 1 H), 2.77 (dd, J = 7.7, 13.6 Hz, 1 H), 2.48−2.43 (m, 2
H), 2.37−2.30 (m, 1 H). 13C NMR (176 MHz, CDCl3) δ 136.5,
128.98, 128.95, 127.2, 77.2, 77.0, 76.8, 57.2, 42.4, 29.7, 26.3.
( )-3-[4-(Dimethylamino)benzyl]-2-(4-methoxyphenyl)-3,4-
dihydropyrrolo[1,2-a]pyrazin-1(2H)-one (20c). The title compound
was prepared from substrate 17 (49 mg, 0.19 mmol), 4-bromo-N,N-
dimethylaniline (82 mg, 0.41 mmol), LiOtBu (33 mg, 0.41 mmol),
Pd(OAc)2 (0.9 mg, 0.004 mmol), and SPhos (5.2 mg, 0.013 mmol)
according to General Procedure 3, using toluene as the solvent rather
than benzotrifluoride. This procedure afforded 63 mg (88%) of the
1
title compound as a green liquid. H NMR (500 MHz, CDCl3) δ
7.33−7.26 (m, 1 H), 7.03 (dd, J = 1.5, 3.9 Hz, 1 H), 6.96 (d, J = 8.8
Hz, 1 H), 6.86 (d, J = 8.3 Hz, 1 H), 6.72 (t, J = 2.0 Hz, 1 H), 6.67 (d, J
= 7.3 Hz, 1 H), 6.29 (dd, J = 2.5, 3.9 Hz, 1 H), 4.19 (dd, J = 4.0, 12.6
Hz, 1 H), 4.05−3.93 (m, 1 H), 3.84 (s, 2 H), 3.03 (dd, J = 4.3, 13.7
Hz, 1 H), 2.92 (s, 6 H), 2.58 (dd, J = 11.3, 13.7 Hz, 1 H); 13C NMR
(126 MHz, CDCl3) δ 158.4, 158.2, 149.5, 134.0, 129.9, 128.7, 124.52,
123.2, 114.5, 114.2, 114.0, 113.0, 109.9, 62.2, 55.5, 45.1, 40.7, 36.0,
29.7; IR (film) 1641 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+
calculated for C23H25N3O2 376.2020; found 376.2028.
Synthesis and Reactivity of Deuterated Substrate 21. (E)-N-(4-
Methoxyphenyl)-pent-4-(5-d)-enamide (21). This reaction was
conducted with the hood light turned off. A flame-dried three-neck
round-bottom flask equipped with a stir bar was cooled under a stream
of nitrogen, wrapped in aluminum foil, charged with THF (5 mL), and
bisdicyclopentylzirconium(IV) dichloride (1.5 g, 5.13 mmol), and
cooled to 0 °C. A solution of lithium triethylborohydride (4.9 mL, 4.9
mmol, × 1.0 M in THF) at 0 °C was added via syringe. The resulting
mixture was warmed to rt and stirred for 2 h with the hood light off.
The reaction mixture was then cooled to 0 °C, a solution of tert-
butyldimethyl(pent-4-yn-1-yloxy)silane (502 mg, 2.52 mmol) in THF
(5 mL) was added dropwise, and the resulting mixture was warmed to
rt and stirred for 30 min. Deuterium oxide (2 mL, 93 mmol) was
added, and the mixture was stirred at rt for 15 min. Then the mixture
was diluted with hexanes (15 mL), filtered through a pad of silica gel,
and concentrated in vacuo. The crude product was purified via flash
chromatography on silica gel using 10% ethyl acetate/hexanes as the
eluent to afford 382 mg (75%) of (E)-tert-butyldimethyl[(pent-4-en-1-
yl-5-d)oxy]silane as a colorless oil. This material was judged to have
( )-2-(4-Methoxyphenyl)-3-(2-methylbenzyl)-3,4-dihydropyrrolo-
[1,2-a]pyrazin-1(2H)-one (20d). The title compound was prepared
from substrate 17 (54 mg, 0.21 mmol), 2-bromotoluene (50 μL, 0.42
mmol), LiOtBu (32 mg, 0.40 mmol), Pd(OAc)2 (0.9 mg, 0.004
mmol), and SPhos (5.4 mg, 0.013 mmol) according to General
Procedure 3. This procedure afforded 63 mg (87%) of the title
1
compound as a white solid, mp 130−131 °C. H NMR (500 MHz,
CDCl3) δ 7.33−7.25 (m, 3 H), 7.13 (ddd, J = 1.8, 6.1, 12.6 Hz, 2 H),
7.12−7.02 (m, 1 H), 7.02−6.86 (m, 2 H), 6.85−6.70 (m, 1 H), 6.31
(dd, J = 2.5, 3.9 Hz, 1 H), 4.24 (dd, J = 4.2, 12.8 Hz, 1 H), 4.16−4.03
(m, 1 H), 3.96 (dd, J = 1.8, 12.7 Hz, 1 H), 3.84 (s, 2 H), 3.10 (dd, J =
4.0, 13.7 Hz, 1 H), 2.76 (dd, J = 11.3, 13.7 Hz, 1 H), 1.96 (s, 3 H); 13C
NMR (126 MHz, CDCl3) δ 158.34, 158.27, 136.4, 135.1, 133.7, 130.8,
130.3, 128.8, 127.2, 126.3, 124.5, 123.2, 114.49, 114.48, 114.2, 110.1,
60.7, 55.5, 45.2, 34.1, 18.9; IR (film) 1641 cm−1. HRMS (ESI+ TOF)
m/z: [M + H]+ calculated for C22H22N2O2 347.1754; found 347.1757.
( )-2-(4-Methoxyphenyl)-3-(pyridin-3-ylmethyl)-3,4-dihydro-
pyrrolo[1,2-a]pyrazin-1(2H)-one (20e). The title compound was
prepared from substrate 17 (51 mg, 0.20 mmol), 3-bromopyridine (40
μL, 0.42 mmol), LiOtBu (34 mg, 0.42 mmol), Pd(OAc)2 (1.0 mg,
0.004 mmol), and SPhos (5.8 mg, 0.014 mmol) according to General
Procedure 3. This procedure afforded 62 mg (94%) of the title
1
undergone 95% d-incorporation. H NMR (500 MHz, CDCl3) δ 5.83
(dt, J = 6.6, 15.4 Hz, 1 H), 5.00 (d, J = 1.6, 17.1 Hz, 1 H), 3.91 (q, J =
7.1 Hz, 2 H), 2.14−2.07 (m, 2 H), 1.63 (qd, J = 4.5, 7.3, 8.1 Hz, 2 H),
1.36−1.12 (m, 9 H), 1.04−0.84 (m, 6 H).
A flame-dried round-bottom flask was cooled under a stream of
nitrogen and charged with (E)-tert-butyldimethyl[(pent-4-en-1-yl-5-
d)oxy]silane (382 mg, 1.9 mmol) and THF (2 mL). A solution of
tetrabutylammonium fluoride (5 mL, 1 M in THF) was added, and the
resulting solution was stirred at rt until the starting material had been
completely consumed as judged by TLC analysis (ca. 16 h). The
mixture was then diluted with diethyl ether (15 mL), extracted with
saturated sodium chloride (5 × 10 mL), and purified via column
chromatography on silica gel using 5% ethyl acetate/hexanes as the
eluent to afford (E)-pent-4-en-5-d-1-ol (143 mg, 84%).
1
compound as a yellow solid, mp 143−145 °C. H NMR (500 MHz,
CDCl3) δ 8.46 (d, J = 4.7 Hz, 1 H), 8.26 (s, 1 H), 7.32 (dt, J = 1.9, 7.8
Hz, 1 H), 7.27−7.16 (m, 3 H), 6.99 (dd, J = 1.5, 3.9 Hz, 1 H), 6.96−
6.88 (m, 2 H), 6.71 (t, J = 2.0 Hz, 1 H), 6.28 (dd, J = 2.5, 3.9 Hz, 1 H),
4.28 (dd, J = 4.1, 12.9 Hz, 1 H), 4.11 (dtd, J = 1.6, 3.1, 3.8, 10.1 Hz, 1
H), 3.88 (dd, J = 1.9, 12.9 Hz, 1 H), 3.80 (s, 3 H), 3.07 (dd, J = 4.6,
13.8 Hz, 1 H), 2.73 (dd, J = 10.6, 13.8 Hz, 1 H); 13C NMR (126 MHz,
CDCl3) δ 158.4, 158.1, 150.1, 148.2, 136.9, 133.6, 132.6, 128.6, 124.3,
123.7, 123.2, 114.6, 114.5, 110.3, 61.4, 55.5, 45.4, 34.4, 29.7; IR (film)
1638 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for
C20H19N3O2 334.1550; found 334.1556.
Jones Reagent was prepared first by cooling a flame-dried 100 mL
round-bottom flask and stir bar under a stream of nitrogen. This vessel
was then charged with chromium(VI) trioxide (13.3 g, 133.0 mmol)
and water (39 mL). The reaction vessel was cooled to room
temperature, and concentrated sulfuric acid (11 mL, 202.4 mmol) was
slowly added, bringing the total volume to 50 mL.
A flame-dried round-bottom flask was cooled under a stream of
nitrogen and charged with (E)-pent-4-en-5-d-1-ol (143 mg, 1.6 mmol)
and acetone (50 mL). Subsequent dropwise addition of Jones Reagent
(4 mL, of prepared stock solution described above) at 0 °C resulted in
a murky solution, which was warmed to rt and stirred overnight. The
mixture was then diluted with water (60 mL) and extracted with
dichloromethane (3 × 15 mL) to afford a solution of (E)-pent-4-
enoic-5-d acid in dichloromethane that was carried on in the next step
without further purification.
( )-2-(4-Methoxyphenyl)-3-(thiophen-2-ylmethyl)-3,4-dihydro-
pyrrolo[1,2-a]pyrazin-1(2H)-one (20f). The title compound was
prepared from substrate 17 (49 mg, 0.19 mmol), 2-bromothiophene
(40 μL, 0.41 mmol), LiOtBu (35 mg, 0.44 mmol), Pd(OAc)2 (1.1 mg,
0.005 mmol), and SPhos (5.8 mg, 0.014 mmol) according to General
Procedure 3. This procedure afforded 60 mg (93%) of the title
1
compound as a yellow solid, mp 161−163 °C. H NMR (500 MHz,
CDCl3) δ 7.30−7.24 (m, 2 H), 7.19−7.08 (m, 1H), 7.03 (dd, J = 1.5,
3.8 Hz, 1 H), 7.01−6.94 (m, 1 H), 6.96 (s, 1 H), 6.95 (s, 1 H), 6.95−
6.82 (m, 2 H), 6.75−6.68 (m, 3 H), 6.29 (dd, J = 2.5, 3.8 Hz, 2 H),
4.28 (dd, J = 4.1, 12.8 Hz, 1 H), 4.12 (ddd, J = 2.0, 4.3, 8.9 Hz, 1 H),
4.12−3.99 (m, 2 H), 3.83 (s, 3 H), 3.25 (dd, J = 4.3, 14.6 Hz, 1 H),
2.98 (dd, J = 11.0, 14.6 Hz, 1 H); 13C NMR (126 MHz, CDCl3) δ
H
DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
The title compound was prepared from the (E)-pent-4-en-5-d-oic
acid solution and p-anisidine (0.7 g, 5.68 mmol) according to General
Procedure 1. This procedure afforded 69 mg (21% over two steps) of
the title compound as a pale brown solid, mp 83−85 °C, with 95%
quenched with saturated aqueous ammonium chloride (3 mL), and
extracted with dichloromethane (3 × 2 mL). The collected organic
layers were then dried over anhydrous sodium sulfate, decanted,
concentrated in vacuo, and subsequently purified by flash chromatog-
raphy on silica gel to afford 175 mg (53%) of ( )-(2S*,1′R*)-tert-
butyl 2-(phenylmethyl-d)pyrrolidine-1-carboxylate as a clear oil. The
compound was obtained as a >20:1 mixture of diastereomers as judged
by 1H NMR analysis. 1H NMR (500 MHz, Chloroform-d) δ 7.52 (s, 1
H), 7.33−7.26 (m, 3 H), 7.21 (dd, J = 8.9, 16.0 Hz, 4 H), 4.06 (s, 1
H), 3.96 (s, 1 H), 3.40−3.35 (m, 2 H), 3.30 (s, 1 H), 3.16 (s, 1 H),
3.06 (d, J = 15.3 Hz, 1 H), 1.80−1.67 (m, 4 H), 1.64 (d, J = 3.2 Hz, 1
H), 1.61−1.56 (m, 1 H), 1.46 (d, J = 4.3 Hz, 1 H), 1.28 (d, J = 6.4 Hz,
1 H).
1
deuterium incorporation. H NMR (700 MHz, CDCl3) δ 7.41−7.35
(m, 2 H), 7.11 (s, 1 H), 6.87−6.81 (m, 2 H), 5.90−5.85 (m, 1 H),
5.12−5.08 (m, 1 H), 3.77 (s, 3 H), 2.50−2.40 (m, 4 H); 13C NMR
(176 MHz, CDCl3) δ 170.3, 136.8, 130.9, 121.7, 114.1, 55.5, 36.6,
29.5; IR (film) 3296.5, 1650.0, 1514.5, 1251.1 cm−1. HRMS (ESI+
TOF) m/z: [M + H]+ calculated for C12H15DNO2 207.1238; found
207.1238.
(
)-(5R*,1′R*)-1-(4-Methoxyphenyl)-5-(phenylmethyl-d)-
pyrrolidin-2-one (22). The title compound was prepared from
substrate 2137 (49 mg, 0.24 mmol), bromobenzene (50 μL, 0.48
mmol), LiOtBu (31 mg, 0.39 mmol), PdBr2 (4.2 mg, 0.016 mmol),
and XPhos (18.2 mg, 0.038 mmol) according to General Procedure 2.
This procedure afforded 30 mg (45%) of the title compound as a
yellow oil. The compound was obtained as a >20:1 mixture of
A flame-dried round-bottom flask was cooled under a stream of
nitrogen and charged with ( )-(2S*,1′R*)-tert-butyl 2-(phenylmethyl-
d)pyrrolidine-1-carboxylate (75 mg, 0.29 mmol), 2 mL of dichloro-
methane, and 2 mL of trifluoroacetic acid. The reaction mixture was
stirred until the starting material had been completely consumed as
judged by TLC analysis (ca. 5 h) and then was quenched with
saturated ammonium hydroxide (10 mL). The layers were separated,
and the aqueous layer was extracted with dichloromethane (3 × 10
mL). The organic layers were combined, dried over sodium sulfate,
and concentrated in vacuo. The resulting crude pyrrolidine was then
N-arylated:40 A flame-dried Schlenk tube equipped with a stir bar was
cooled under a stream of nitrogen and charged with Pd(OAc)2 (2.0
mg, 0.009 mmol), (2-biphenyl)di-tert-butylphosphine (10.2 mg, 0.038
mmol), sodium tert-butoxide (90.8 mg, 0.94 mmol), 4-bromoanisole
(50 μL, 0.40 mmol), and a solution of the crude pyrrolidine in toluene
(1 mL). The mixture was heated to 110 °C until the starting material
had been completely consumed as judged by TLC analysis. The
reaction mixture was then worked up by addition of saturated aqueous
ammonium chloride (2 mL) and extracted with ethyl acetate (3 × 3
mL). The organic layers were reserved and dried over sodium sulfate,
and solvent was removed in vacuo. The product was then purified by
flash chromatography on silica gel to afford 23 mg (35% yield over two
steps) of the title compound as a clear oil. The compound was
1
diastereomers as judged by H NMR analysis. Data are for the major
isomer. 1H NMR (700 MHz, CDCl3) δ 7.41−7.34 (m, 2 H), 7.28 (d, J
= 7.4 Hz, 2 H), 7.28−7.19 (m, 1 H), 7.13−7.08 (m, 2 H), 6.99−6.93
(m, 2 H), 4.40−4.31 (m, 1 H), 3.82 (s, 3 H), 2.56 (d, J = 9.1 Hz, 1 H),
2.45−2.34 (m, 2 H), 2.16−2.08 (m, 1 H), 1.91−1.85 (m, 1 H). 13C
NMR (176 MHz, CDCl3) δ 174.4, 157.6, 136.8, 130.4, 129.2, 128.6,
126.7, 125.7, 121.7, 114.5, 114.0, 77.2, 77.0, 76.9, 61.2, 55.5, 39.2, 39.1,
30.9, 23.4. IR (film) 1679.7, 1508.8, 1242.8, 909.9 cm−1. HRMS (ESI+
TOF) m/z: [M + H]+ calculated for C18H18DNO2 283.1551; found
283.1557. The stereochemistry of this compound was assigned by
reduction to the corresponding pyrrolidine 26 and then comparison of
the NMR spectra of 26 to its diastereomer 27, which was prepared via
Pd-catalyzed carboamination of tert-butyl pent-4-enoyl carbamate
followed by deprotection and N-arylation as described below.
(
)-(2R*,1′R*)-1-(4-Methoxyphenyl)-2-(phenylmethyl-d)-
pyrrolidine (26). A flame-dried round-bottom flask was cooled with
nitrogen and charged with pyrrolidin-2-one 22 (30 mg, 0.11 mmol)
and tetrahydrofuran (0.5 mL). A solution of lithium aluminum hydride
(0.5 mL, 0.5 mmol, 1 M in THF) was then added, and the resulting
mixture was stirred at rt for 3 min followed by heating to 45 °C and
stirring until the starting material had been completely consumed as
judged by TLC analysis (ca. 3 h). The solution was then was cooled to
0 °C, quenched with H2O (0.5 mL), and diluted with diethyl ether (5
mL). A solution of aqueous NaOH (0.5 mL, 10 M) was added, and an
insoluble white material precipitated. The organic supernatant was
decanted, and the precipitate was washed with diethyl ether (5 mL).
The combined organic washes were dried over anhydrous sodium
sulfate, filtered, and concentrated in vacuo. The crude product was
purified via column chromatography on silica gel using 5% ethyl
acetate/hexanes as the eluent to afford 7 mg (25%) of the title
compound as a clear oil. The compound was obtained as a >20:1
1
obtained as a >20:1 mixture of diastereomers as judged by H NMR
1
analysis. H NMR (500 MHz, CDCl3) δ 7.34−7.17 (m, 5 H), 6.95−
6.86 (m, 2 H), 6.68−6.64 (m, 2 H), 3.92−3.87 (m, 1 H), 3.81 (s, 3 H),
3.44−3.36 (m, 1 H), 3.18−3.10 (m, 1 H), 3.09−3.02 (m, 1 H), 1.92−
1.82 (m, 2 H), 1.30 (d, J = 2.3 Hz, 2 H). 13C NMR (126 MHz,
CDCl3) δ 129.3, 128.3, 126.1, 125.3, 115.2, 113.8, 112.6, 77.2, 77.0,
76.7, 60.1, 56.0, 55.5, 49.0, 29.6, 28.7, 23.2. IR (film) 1510.6, 1241.8,
1039.6 cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for
C18H20DNO 269.1759; found 269.1759.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
1
mixture of diastereomers as judged by H NMR analysis. H NMR
(700 MHz, CDCl3) δ 7.30 (t, J = 7.7 Hz, 2 H), 7.29−7.22 (m, 3 H),
6.93−6.79 (m, 2 H), 6.65 (dd, J = 3.0, 9.8 Hz, 2 H), 3.91−3.86 (m, 1
H), 3.83 (s, 3 H), 3.43−3.37 (m, 1 H), 3.16−3.10 (m, 1 H), 2.53 (t, J
= 10.2 Hz, 1 H), 1.93−1.81 (m, 4 H); 13C NMR (176 MHz, CDCl3) δ
150.7, 142.0, 139.6, 129.3, 128.3, 126.1, 115.2, 112.6, 77.2, 77.0, 76.8,
60.2, 56.0, 55.7, 49.0, 29.6, 23.2. IR (film) 1510.6, 1241.8, 1039.6
cm−1. HRMS (ESI+ TOF) m/z: [M + H]+ calculated for C18H20DNO
269.1759; found 269.1758.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.7b00041.
Descriptions of stereochemical assignments and copies of
1H and 13C NMR spectra for new compounds (PDF)
AUTHOR INFORMATION
■
Corresponding Author
(
)-(2S*,1′R*)-1-(4-Methoxyphenyl)-2-(phenylmethyl-d)-
*E-mail: jpwolfe@umich.edu.
pyrrolidine (27). Prepared following previously reported procedures
that have been shown to afford syn-addition products37 via Pd-
catalyzed carboamination reactions of carbamate substrates. A flame-
dried Schlenk tube equipped with a stir bar was cooled under a stream
of nitrogen and charged with tert-butyl pent-4-enoyl carbamate (233
mg, 0.89 mmol), Pd(OAc)2 (5.4 mg, 0.024 mmol), DPEphos (20.1
mg, 0.037 mmol), and NaOtBu (209 mg, 2.17 mmol). The tube was
purged with nitrogen, and toluene (4 mL) and bromobenzene (100
μL, 0.95 mmol) were added via syringe. The mixture was heated to
100 °C with stirring until the reaction was complete as determined by
TLC analysis. The reaction mixture was cooled to room temperature,
ORCID
John P. Wolfe: 0000-0002-7538-6273
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors thank the NIH-NIGMS (GM098314) for financial
support of this work.
I
DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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DOI: 10.1021/acs.joc.7b00041
J. Org. Chem. XXXX, XXX, XXX−XXX