Photoredox activation for the direct β-arylation of ketones and aldehydes

Article abstract of DOI:10.1126/science.1232993

The direct β-activation of saturated aldehydes and ketones has long been an elusive transformation. We found that photoredox catalysis in combination with organocatalysis can lead to the transient generation of 5π-electron β-enaminyl radicals from ketones and aldehydes that rapidly couple with cyano-substituted aryl rings at the carbonyl β-position. This mode of activation is suitable for a broad range of carbonyl β-functionalization reactions and is amenable to enantioselective catalysis.

Full text of DOI:10.1126/science.1232993

www.sciencemag.org/cgi/content/full/339/6127/1593/DC1
Supplementary Materials for
Photoredox Activation for the Direct β-Arylation of Ketones and Aldehydes
Michael T. Pirnot, Danica A. Rankic, David B. C. Martin, David W. C. MacMillan*
*To whom correspondence should be addressed. E-mail: dmacmill@princeton.edu
Published 29 March 2013, Science 339, 1593 (2013)
DOI: 10.1126/science.1232993
This PDF file includes:
Materials and Methods
Supplementary Text
Fig. S1
Table S1
NMR Spectra
References and Notes

Supplementary Material
S 2
Materials and Methods.
Commercial reagents were purified prior to use following the guidelines of Perrin and Armarego
(
27). All aldehydes were distilled or purified via flash chromatography prior to use. All solvents
were purified by passage through columns of activated alumina. Organic solutions were
concentrated under reduced pressure on a Büchi rotary evaporator using an acetone-dry ice bath
for volatile compounds. Chromatographic purification of products was accomplished by flash
chromatography on silica gel (Fluka, 230-400 mesh). Thin layer chromatography (TLC) was
performed on Analtech Uniplate 250 m silica gel plates. Visualization of the developed
chromatogram was performed by fluorescence quenching, p-anisaldehyde, potassium
1
13
permanganate, or ceric ammonium molybdate stain. H and C NMR spectra were recorded on a
Bruker 500 (500 and 125 MHz) instrument, and are internally referenced to residual protio
1
solvent signals (note: CDCl
3
referenced at 7.27 and 77.0 ppm respectively). Data for H NMR
are reported as follows: chemical shift ( ppm), integration, multiplicity (s = singlet, d = doublet,
13
t = triplet, q = quartet, m = multiplet), coupling constant (Hz) and assignment. Data for C NMR
are reported in terms of chemical shift and no special nomenclature is used for equivalent
carbons. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are
1
reported in terms of frequency of absorption (cm ). High resolution mass spectra were obtained
at Princeton University mass spectrometry facilities. Supercritical fluid chromatography (SFC)
was performed on a Berger Minigram equipped with a diode array UV detector (λ = 214–280 nm)
using a chiral column (25 cm) and guard column (5 cm) as noted for each compound. Optical
D
rotations were measured on a Jasco P-1010 polarimeter with [α] values reported in degrees;
concentration (c) is in g/100 mL. All aldehydes were used from commercial suppliers or prepared
using standard literature procedures. All cyano aromatics were used from commercial suppliers or
prepared using standard literature procedures.
Supplementary Text
Synthesis of Starting Material Aldehydes
General Procedure - To a solution of the respective alcohol in DCM (0.5 M) was added TEMPO
(0.10 equiv) and iodobenzene diacetate (1.1 equiv). The reaction mixture was stirred for 12 h and
then quenched with a saturated solution of sodium thiosulfate. The layers were separated and the
aqueous layer was extracted with DCM three times. The combined organic layers were then dried

Supplementary Material
S 3
with sodium sulfate and concentrated in vacuo. Purification of the crude product by flash
chromatography on silica gel using the indicated solvent system afforded the desired aldehyde.
Oct-7-ynal. Prepared according to the general procedure using 505 mg of oct-7-yn-1-ol (4.0
mmol, 1.00 equiv), 31 mg of TEMPO (0.20 mmol, 0.05 equiv), 1.42 g of iodobenzene diacetate
(4.4 mmol, 1.10 equiv), and 16 mL of DCM. After 12 h, the reaction mixture was subjected to the
workup protocol outlined in the general procedure and purified by flash chromatography (silica
gel: 10% to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (373 mg,
3.0 mmol, 75%). The spectral data for the title compound were identical to the previously
reported data (28).
(2,2-Diphenylethyl)(propan-2-yl)amine. To a solution of diphenylacetaldehyde (1.05 mL, 5.84
mmol, 1.0 equiv), isopropylamine (1.00 mL, 11.7 mmol, 2.0 equiv) and acetic acid (33 L, 0.58
mmol, 0.1 equiv) in MeOH (14.6 mL) was added 5Å MS (300 mg). After 1h of stirring at room
temperature, sodium triacetoxyborohydride (3.71 g, 17.5 mmol, 3.0 equiv) was added in 3
portions over 20 h. The reaction mixture was diluted with EtOAc (50 mL) and 1M NaOH (50
mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The

Supplementary Material
S 4
combined organic extracts were washed with brine, dried over Na
2
SO
4
and concentrated in vacuo.
Purification of the crude product by flash chromatography (silica gel: 0% to 3% NH
4
OH/MeOH
in DCM) to afford the title compound as a clear oil (640 mg, 2.69 mmol, 46%). IR (film) 3026,
–
1 1
2
963, 1494, 1450, 1174, 740, 697 cm ; H NMR (500 MHz, CDCl
.25-7.19 (m, 2H, PhH), 4.20 (t, J = 7.7 Hz, 1H, CH CHPh ), 3.24 (d, J = 7.7 Hz, 2H,
CHPh ), 2.83 (hept, J = 6.2 Hz, 1H, (CH CHN), 1.03 (d, J = 6.2 Hz, 6H, (CH
NMR (125 MHz, CDCl 142.9, 128.6, 128.0, 126.5, 52.2, 51.2, 48.6, 22.9; HRMS (ESI) exact
3
)
7.35–7.25 (m, 8H, PhH),
7
2
2
1
3
CH
2
2
3
)
2
3 2
) CHN); C
3
)
+
mass calculated for [M+H] (C17H21N) requires m/z 240.1752, found m/z 240.1751.
DFT Calculations
(1). Complete reference for Ref. 25.
Gaussian 09, Revision B.01, M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci, G. A. Petersson, H. Nakatsuji, M.
Caricato, X. Li, H. P. Hratchian, A. F. Izmaylov, J. Bloino, G. Zheng, J. L. Sonnenberg, M. Hada,
M. Ehara, K. Toyota, R. Fukuda, J. Hasegawa, M. Ishida, T. Nakajima, Y. Honda, O. Kitao, H.
Nakai, T. Vreven, J. A. Montgomery, Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E.
Brothers, K. N. Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K. Raghavachari,
A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M. Cossi, N. Rega, J. M. Millam, M. Klene, J.
E. Knox, J. B. Cross, V. Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L. Martin, K. Morokuma, V. G.
Zakrzewski, G. A. Voth, P. Salvador, J. J. Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J.
B. Foresman, J. V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT, 2010.
(2) Computational results with solvation corrections.

Supplementary Material
S 5
Solvation energy corrections were calculated by UB3LYP-6-311+G(d) single point
calculations with the IEFPCM solvation model in DMSO for the structures reported in the main
text. The solvation-corrected energy profile is summarized in Figure S1 and Table S1. In the
solvation-corrected energy diagram, the maximum deviations from the gas-phase results were
roughly 10 kcal/mol.

Supplementary Material
S 6
(3). UB3LYP electronic energies (a.u.).
Geometry E(B3LYP)
S1
S2
S3
S4
-445.9683481
-445.4896965
-445.4920977
-445.5055125
-345.4132425
DABCO
DABCOH+ -345.8701448
(4). UB3LYP geometries for all the optimized compounds.
S1
C
C
C
C
H
H
H
H
H
H
H
H
N
C
C
C
C
H
C
H
H
C
H
H
H
H
H
H
-1.78981 -1.20521 0.05526
-3.21234 -0.71277 -0.21782
-3.20148 0.72583 0.31166
-1.80924 1.23644 -0.06854
-1.68343 -1.62438 1.06184
-1.4407 -1.95183 -0.65785
-3.41551 -0.72853 -1.29185
-3.95645 -1.34298 0.26883
-3.98735 1.3469 -0.11793
-3.32369 0.74023 1.39792
-1.78761 1.6437 -1.08433
-1.42118 1.98777 0.61811
-0.95183 0.01812 -0.0323
0.38578 0.01528 -0.04079
1.09718 1.22103 -0.1647
1.1267 -1.29477 0.10673
2.57835 1.31089 -0.10821
0.55178 2.14199 -0.33775
2.61535 -1.19411 -0.25662
1.01527 -1.62619 1.14823
0.64722 -2.06558 -0.50112
3.26358 0.03252 0.3842
2.85599 2.18482 0.49463
2.92843 1.57029 -1.12237
3.11658 -2.11047 0.06164
2.72356 -1.14493 -1.34593
4.3294 0.0725 0.15162
3.18615 -0.031 1.4754

Supplementary Material
S 7
S2
C
C
C
C
H
H
H
H
H
H
H
N
C
C
C
C
H
C
H
H
C
H
H
H
H
H
H
1.82737 1.161
-0.10684
3.24052 0.61309 -0.36074
3.23032 -0.76899 0.32134
1.79589 -1.18084 0.18251
1.78801 1.76582 0.80821
1.47257 1.78242 -0.93211
3.40047 0.49297 -1.43574
4.01572 1.28124 0.0203
3.92921 -1.47028 -0.14415
3.53321 -0.68079 1.37858
1.36074 -2.04541 0.66904
1.0021 -0.05048 0.04312
-0.39343 -0.05964 -0.04925
-1.0831 -1.19275 -0.3081
-1.09255 1.25403 0.23905
-2.58709 -1.28572 -0.28818
-0.53653 -2.09394 -0.56832
-2.58271 1.22007 -0.12419
-0.97419 1.49816 1.30447
-0.60925 2.07221 -0.30412
-3.24101 -0.0678 0.37333
-2.89518 -2.20279 0.23003
-2.96893 -1.39506 -1.31503
-3.08072 2.10194 0.29213
-2.69315 1.28379 -1.21384
-4.31743 -0.05622 0.1726
-3.12454 -0.13549 1.46247
S3
C
C
C
C
H
H
H
H
H
H
H
N
C
C
C
-1.79425 -1.16134 0.09943
-3.22585 -0.7891 -0.13046
-3.24172 0.69991 0.26643
-1.82378 1.18853 -0.06985
-1.37439 -2.13285 -0.11455
-3.52182 -0.90764 -1.18752
-3.92563 -1.38896 0.45827
-4.01007 1.2786 -0.25027
-3.41856 0.79377 1.34119
-1.7634 1.64011 -1.06838
-1.45297 1.92524 0.64825
-0.99858 -0.02643 -0.028
0.3888 0.03063 -0.06511
1.06626 1.20203 -0.17277
1.10472 -1.29788 0.04611

Supplementary Material
S 8
C
H
C
H
H
C
H
H
H
H
H
H
2.56991 1.30353 -0.13187
0.52355 2.13375 -0.28965
2.61232 -1.19885 -0.22309
0.91918 -1.71832 1.0441
0.66532 -2.0121 -0.65894
3.22148 0.03893 0.43558
2.86152 2.17607 0.46577
2.96978 1.49783 -1.13962
3.10434 -2.11288 0.12506
2.78446 -1.14683 -1.30531
4.30545 0.06485 0.28178
3.05595 -0.00407 1.51947
S4
C
C
C
C
H
H
H
H
H
H
H
H
N
C
C
C
C
H
C
H
H
C
H
H
H
H
H
1.75059 -1.2065 -0.07537
1.77642 1.21238 0.12067
3.19615 0.67394 0.33009
3.16196 -0.68729 -0.37915
1.7406 -1.79104 0.85689
1.36975 -1.85505 -0.86972
1.69988 1.7967 -0.80951
1.4529 1.86411 0.93955
3.96029 1.3471 -0.06462
3.39316 0.53956 1.39862
3.28611 -0.55318 -1.4586
3.94102 -1.37301 -0.03843
0.94848 0.01188 0.0522
-0.4294 0.05403 -0.02434
-1.14404 1.25666 -0.07223
-1.18816 -1.25286 -0.06345
-2.52735 1.31833 -0.16581
-0.59535 2.19341 -0.04958
-2.62149 -1.0967 0.47033
-1.2237 -1.63826 -1.09427
-0.66859 -2.01821 0.52222
-3.35892 0.06843 -0.20473
-3.01788 2.28362 -0.23247
-3.17008 -2.03428 0.33181
-2.5766 -0.91029 1.54927
-4.32752 0.23035 0.28297
-3.59798 -0.20727 -1.24553
DABCO
C
C
-0.78196 0.37252 -1.33249
0.78198 0.37258 -1.33247

Supplementary Material
S 9
H
H
H
H
C
H
H
C
H
H
C
H
H
C
H
H
N
N
-1.18521 -0.33846 -2.05996
-1.18515 1.35779 -1.58558
1.1853 -0.33821 -2.06008
1.1851 1.35792 -1.58532
-0.78207 -1.34046 0.34379
-1.18526 -1.61462 1.32339
-1.1855 -2.05225 -0.38281
0.78191 -1.3406 0.34363
1.18527 -1.61504 1.32307
1.18505 -2.0523 -0.38322
0.78211 0.96789 0.98891
1.18547 0.69439 1.96865
1.18564 1.95326 0.73671
-0.78196 0.9681 0.98883
-1.18552 0.69492 1.96858
-1.1852 1.95353 0.73635
-1.28702 0.
-0.00006
1.28702 -0.00016 -0.00008
+
DABCO-H
C
C
H
H
H
H
C
H
H
C
H
H
C
H
H
C
H
H
N
N
H
-0.7407 -0.52191 1.33913
0.81773 -0.50389 1.29367
-1.15993 0.12852 2.1072
-1.15951 -1.52078 1.46326
1.21502 0.1309 2.0863
1.21526 -1.50735 1.4486
-0.73724 1.42228 -0.21869
-1.15451 1.76237 -1.16678
-1.15601 2.03072 0.58324
0.82044 1.37063 -0.2094
1.2198 1.73886 -1.1549
1.21844 2.00588 0.5825
0.82041 -0.86825 -1.08142
1.21986 -0.50057 -2.02707
1.21775 -1.87194 -0.9272
-0.73789 -0.89929 -1.12291
-1.15504 -0.50884 -2.05143
-1.15687 -1.88971 -0.9434
-1.22713 0.00102 -0.00147
1.2879 -0.00064 0.00149
-2.24617 0.00177 -0.00268

Supplementary Material
S 10
Optimization Studies
Photocatalyst
Ir(ppy) , no light
no photocatalyst
Product %
0%
3
0%
Ru(bpy)
Ir(ppy)
3
Cl
2
0%
90%
3
Using 0.20 equiv, iPrNHBn amine, 5 equiv DABCO, 0.20
equiv HOAc, 3 equiv H O, 1.4 equiv octanal, 1.0 equiv
,4-DCB, 0.50 M, DMPU at 23 °C.
2
1
Amine catalyst
no amine catalyst
pyrrolidine
Product %
0%
31%
diethylamine
MeNHBn
70%
78%
iPrNHBn
90%
Using 0.01 equiv Ir(ppy)
HOAc, 3 equiv H
DCB, 0.50 M DMPU at 23 ºC.
3
, 5 equiv DABCO, 0.20 equiv
2
O, 1.4 equiv octanal, 1.0 equiv 1,4-
Table S1. Optimization Studies
1
*
% Yields calculated by H-NMR with methyl benzoate as an internal standard.
General Procedure for the -Arylation of Aldehydes: An oven-dried 8 mL vial equipped with
2
a Teflon septum and magnetic stir bar was charged with tris[2-phenylpyridinato-C ,N]iridium(III)
(10.0 mol, 0.01 equiv), the corresponding aromatic nitrile (1.00 mmol, 1.0 equiv), the
corresponding aldehyde (1.40–3.00 mmol, 1.4–3.0 equiv, if solid), and 1,4-
diazabicyclo[2.2.2]octane (5.00 mmol, 5.0 equiv). The vial was purged with a stream of nitrogen
and 2.0 mL of DMPU was added via syringe, followed by the corresponding aldehyde (1.40–3.00

Supplementary Material
S 11
mmol, 1.4–3.0 equiv, if liquid), acetic acid (0.20 mmol, 0.20 equiv), water (3.00 mmol, 3.00
equiv) and N-Isopropylbenzylamine (0.20 mmol, 0.20 equiv). The reaction mixture was then
cooled to –78 ºC and degassed via vacuum evacuation (5 min), backfilled with nitrogen, and
warmed to room temperature. This process was repeated three times. After the reaction was
thoroughly degassed, the vial was placed approximately 2 cm from a 26 W fluorescent lamp.
After the indicated time period, the reaction mixture was diluted with ethyl acetate and added to a
separatory funnel containing 25 mL of a 1 M aqueous solution of NaOH. The layers were
separated and the aqueous layer was extracted with EtOAc (3 10 mL). The combined organic
2 4
extracts were dried over Na SO and concentrated in vacuo. Purification of the crude product by
flash chromatography on silica gel using the indicated solvent system afforded the desired -
arylated aldehyde product.
4
-(1-Oxooctan-3-yl)benzonitrile. Prepared according to the general procedure using 6.6 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of terephthalonitrile
(
1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 219 L of octanal (1.40
mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water
3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU.
(
After 26 h, the reaction mixture was subjected to the workup protocol outlined in the general
procedure and purified by flash chromatography (silica gel: 10% to 100% ethyl acetate in
hexanes) to afford the title compound as a clear oil (197 mg, 0.86 mmol, 86%). IR (film) 2928,
–
1 1
2
1
228, 1717, 1466, 1417, 1374, 1242, 1045, 834, 733 cm ; H NMR (500 MHz, CDCl
H, CHO), 7.58 (d, J = 8.1 Hz, 2H, ArH), 7.31 (d, J = 8.1 Hz, 2H, ArH), 3.30–3.19 (m, 1H,
CHO), 1.75–1.50 (m, 2H, CH(Ph-4-CN)CH (CH CH ),
); C NMR (125
200.8, 150.0, 132.4, 128.4, 118.9, 110.3, 39.8, 36.1, 31.6, 26.9, 22.4, 14.0, 12.7;
3
) 9.66 (s,
CH(Ph-4-CN)), 2.82-2.69 (m, 2H, CH
.36–1.12 (m, 6H, CH(Ph-4-CN)CH (CH
MHz, CDCl
2
2
2
)
3
3
1
3
1
2
2 3 3 2 3 3
) CH ), 0.87–0.70 (m, 3H, (CH ) CH
3
)

Supplementary Material
HRMS (ESI) exact mass calculated for [M+H] (C15
S 12
+
H
20NO) requires m/z 230.1545, found m/z
230.1545.
4
-(1-Cyclohexyl-3-oxopropyl)benzonitrile. Prepared according to the general procedure using
2
6
.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 196 mg
of 3-cyclohexylpropanal (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.200 mmol,
0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.200 mmol, 0.20
equiv) and 2.0 mL of DMPU. After 46 h, the reaction mixture was subjected to the workup
protocol outlined in the general procedure and purified by flash chromatography (silica gel: 10%
to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (192 mg, 0.79 mmol,
–
1 1
7
9
1
9%). IR (film) 2924, 2852, 2227, 1722, 1607, 1449, 840 cm ; H NMR (500 MHz, CDCl
.55 (s, 1H, CHO), 7.51 (d, J = 8.1 Hz, 2H, ArH), 7.19 (d, J = 8.1 Hz, 2H, ArH), 3.04–2.95 (m,
H, CH(Ph-4-CN)), 2.85 (dd, J = 4.5, 17.2 Hz, 1H, CH CHO), 2.69 (dd, J = 9.1, 16.7 Hz, 1H,
CHO), 1.76–1.48 (m, 4H, cycH), 1.48-1.27 (m, 2H, cycH), 1.20-0.92 (m, 3H, cycH), 0.91-
3
)
2
CH
2
1
3
0
4
.62 (m, 2H, cycH); C NMR (125 MHz, CDCl
3
)
201.3, 148.9, 132.2, 129.2, 119.0, 110.3,
+
6.9, 45.9, 42.8, 31.0, 30.7, 26.3; HRMS (ESI) exact mass calculated for [M+H] (C16
H20NO)
requires m/z 242.1545, found m/z 242.1548.

Supplementary Material
S 13
4
-(4,4-dimethyl-1-oxopentan-3-yl)benzonitrile. Prepared according to the general procedure
2
using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 195 L
of 4,4-dimethylpentanal (1.40 mmol, 1.4 equiv), 64 mg of (2,2-diphenylethyl)(propan-2-yl)amine
(0.25 mmol, 0.25 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20
mmol, 0.20 equiv) and 2.0 mL of DMPU (29). After 48 h, the reaction mixture was diluted with
DCM (40 mL) and added to a separatory funnel containing 25 mL of a 1 M aqueous solution of
NaOH. The layers were separated and the aqueous layer was extracted with DCM (2 10 mL).
2 4
The combined organic extracts were washed with brine (40 mL), dried over Na SO , filtered, and
concentrated in vacuo to afford the crude mixture. Purification of the crude mixture by flash
chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) afforded the title compound as
a light yellow oil (95 mg, 0.44 mmol, 44%). IR (film) 2963, 2227, 1722, 1607, 1367, 1223, 842
–
1
1
cm ; H NMR (500 MHz, CDCl
3
)
9.59 (t, J = 1.8 Hz, 1H, CHO), 7.59 (d, J = 8.3 Hz, 2H,
ArH), 7.29 (d, J = 8.3 Hz, 2H, ArH), 3.16–3.10 (m, J = 8.4, 1H, CH(Ph-4-CN)), 2.91 (dd, J =
1
3
8
1
.4, 1.8 Hz, 2H, CH
2
CHO), 0.90 (s, 9H, C(CH
3
)
3
); C NMR (125 MHz, CDCl
3
)
201.1, 147.2,
+
31.7, 130.1, 118.8, 110.5, 49.9, 44.5, 33.8, 27.8; HRMS (ESI) exact mass calculated for [M+H]
(
C
14
H18NO) requires m/z 216.1388, found m/z 216.1382.

Supplementary Material
S 14
4
-(1-(Benzyloxy)-5-oxopentan-3-yl)benzonitrile. Prepared according to the general procedure
2
using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 269 mg
of 5-(benzyloxy)pentanal (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol,
0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20
equiv) and 2.0 mL of DMPU. After 66 h, the reaction mixture was subjected to the workup
protocol outlined in the general procedure and purified by flash chromatography (silica gel: 10%
to 100% ethyl acetate in hexanes) to afford the title compound as a clear oil (220 mg, 0.75 mmol,
–
1 1
7
5%). IR (film) 2935, 2865, 2228, 1717, 1454, 1363, 1275, 1096, 1072, 736, 698 cm ; H NMR
500 MHz, CDCl 9.62 (s, 1H, CHO), 7.55 (d, J = 8.3 Hz, 2H, ArH), 7.36–7.24 (m, 7H, ArH),
.37 (dd, J = 11.8, 29.1 Hz, 2H, OCH Ph), 3.55–3.46 (m, 1H, CH(Ph-4-CN)), 3.35 (dt, J = 5.3,
.3, 10.4 Hz, 1H, CH OBn), 3.19 (dt, J = 4.9, 9.0, 9.3 Hz, 1H, CH OBn), 2.86–2.69 (m, 2H,
CHO), 2.05–1.95 (m, 1H, CH CH OBn), 1.86–1.75 (m, 1H, CH
(
3
)
4
5
2
2
2
13
CH
2
2
2
2
CH
2
OBn); C NMR (125
MHz, CDCl
3
)
200.5, 149.3, 138.2, 132.7, 128.66, 128.65, 128.00, 127.99, 119.0, 110.7, 73.2,
+
6
2
7.2, 50.0, 36.7, 36.2; HRMS (ESI) exact mass calculated for [M+H] (C19
H20NO
2
) requires m/z
94.1494, found m/z 294.1497.
(
Z)-4-(1-Oxonon-6-en-3-yl)benzonitrile. Prepared according to the general procedure using 6.6
2
mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of

Supplementary Material
S 15
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 233 L
of (Z)-non-6-enal (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20
equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and
2.0 mL of DMPU. After 48 h, the reaction mixture was subjected to the workup protocol outlined
in the general procedure and purified by flash chromatography (silica gel: 10% to 100% ethyl
acetate in hexanes) to afford the title compound as a clear oil (184 mg, 0.76 mmol, 76%). IR
-
1 1
(
film) 2963, 2228, 1722, 1455, 1417, 909, 836 cm ; H NMR (500 MHz, CDCl
CHO), 7.63 (d, J = 8.3 Hz, 2H, ArH), 7.34 (d, J = 8.2 Hz, 2H, ArH), 5.44–5.35 (m, 1H,
CH CHCHCH ), 5.31–5.22 (m, 1H, CH CHCHCH ), 3.33–3.21 (m, 1H, CH(Ph-4-CN)), 2.81-
.67 (m, 2H, CH CHO), 1.94-1.65 (m, 6H, CH CH CHCHCH ), 0.92 (t, J = 7.54 Hz, 3H,
CH CHCHCH CH
3
)
9.69 (s, 1H,
2
2
2
2
2
2
2
2
2
13
2
2
3
); C NMR (125 MHz, CDCl
3
)
200.6 149.6, 133.0, 132.7, 128.6, 127.6,
+
119.0, 110.7, 50.4, 39.4, 36.2, 24.8, 20.7, 14.4; HRMS (ESI) exact mass calculated for [M+H]
(
19
C H20NO) requires m/z 242.1545, found m/z 242.1540.
4
-(1-Oxooct-7-yn-3-yl)benzonitrile. Prepared according to the general procedure using 6.6 mg
2
of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of terephthalonitrile
(1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 106 mg of sodium
carbonate (1.00 mmol, 1.00 equiv), 174 mg of oct-7-ynal (1.40 mmol, 1.4 equiv), 33 L of N-
isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L
of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 46 h, the reaction mixture
was subjected to the workup protocol outlined in the general procedure and purified by flash
chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) to afford the title compound
as a clear oil (149 mg, 0.66 mmol, 66%). IR (film) 3302, 2942, 2228, 1720, 1417, 1276, 1261,
–1 1
9
10, 834 cm ; H NMR (500 MHz, CDCl
3
)
9.65 (s, 1H, CHO), 7.58 (d, J = 8.2 Hz, 2H, ArH),

Supplementary Material
S 16
7
.29 (d, J = 8.2 Hz, 2H, ArH), 3.31–3.21 (m, 1H, CH(Ph-4-CN)), 2.82–2.70 (m, 2H, CH
.16–2.06 (m, 2H, CH(Ph-4-CN)CH (CH
(CH CCH), 1.84–1.62 (m, 2H, CH(Ph-4-CN)CH
CH(Ph-4-CN)CH
2
CHO),
2
2
2
)
2
CCH), 1.95–1.88 (m, 1H, CH(Ph-4-
(CH CCH), 1.44-1.18 (m, 2H,
CN)CH
2
2
)
2
2
2 2
)
1
3
2
(CH
2
)
2
CCH); C NMR (125 MHz, CDCl
3
) 200.5, 149.4, 132.6, 128.6, 118.8,
+
111.0, 83.9, 69.2, 50.7, 39.5, 35.1, 26.2, 18.2; HRMS (ESI) exact mass calculated for [M+H]
(
15
C H16NO) requires m/z 226.1232, found m/z 226.1232.
4
-(3-Hydroxy-1-(4-methoxyphenyl)propyl)benzonitrile. Prepared according to the general
2
procedure using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128
mg of terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv),
230 mg of 3-(4-methoxyphenyl)propanal (1.40 mmol, 1.4 equiv), 33
L of N-
isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L
of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 45 h, the reaction mixture
was transferred to a 25 mL round-bottom flask and diluted with 8 mL of DCM and 2 mL of
MeOH. The reaction mixture was then cooled to 0 ºC and 189 mg of sodium borohydride (5.00
mmol, 5.00 equiv) was added to reduce the resulting aldehyde to the respective alcohol. The
reaction mixture was stirred for 30 min and then diluted with ethyl acetate and added to a
separatory funnel containing 25 mL of a saturated aqueous solution of NaCl. The layers were
separated and the aqueous layer was extracted with EtOAc (3 10 mL). The combined organic
2 4
extracts were then dried with Na SO and concentrated in vacuo. Purification of the crude product
by flash chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) afforded the title
compound as a clear oil (235 mg, 0.88 mmol, 88%). IR (film) 3418, 2935, 2227, 1608, 1510,
–
1 1
1
246, 1178, 1030, 825, 733 cm ; H NMR (500 MHz, CDCl
3
)
7.51 (d, J = 8.3 Hz, 2H, PhH-4-
CN), 7.30 (d, J = 8.2 Hz, 2H, PhH-4-CN), 7.10 (d, J = 8.7 Hz, 2H, PhH-4-OMe), 6.80 (d, J = 8.7

Supplementary Material
S 17
Hz, 2H, PhH-4-OMe), 4.15 (t, J = 7.9 Hz, 1H, (Ph-4-OMe)CH(Ph-4-CN)), 3.73 (s, 3H, (Ph-4-
1
3
OCH
CDCl
HRMS (ESI) exact mass calculated for [M+H] (C17
3
), 3.54 (t, J = 6.32 Hz, 2H, CH
2 2 2
OH), 2.31–2.15 (m, 2H, CH CH OH); C NMR (125 MHz,
3
)
158.5, 150.8, 135.0, 132.5, 123.0, 128.7, 119.2, 114.2, 110.0, 60.5, 55.4, 46.5, 37.9;
+
H
2
18NO ) requires m/z 268.1338, found m/z
268.1344.
4
-(3-Hydroxy-1-(1-methyl-1H-indol-3-yl)propyl)benzonitrile. Prepared according to the
2
general procedure using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01
equiv), 128 mg of terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol,
5.00 equiv), 106 mg of sodium carbonate (1.00 mmol, 1.00 equiv), 262 mg of 3-(1methyl-1H-
indol-3-yl)propanal (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20
equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and
2.0 mL of DMPU (30). After 57 h, the reaction mixture was transferred to a 25 mL round-bottom
flask and diluted with 8 mL of DCM and 2 mL of MeOH. The reaction mixture was then cooled
º
to 0 C and 189 mg of sodium borohydride (5.00 mmol, 5.00 equiv) was added to reduce the
resulting aldehyde to the respective alcohol. The reaction mixture was stirred for 30 min and then
diluted with ethyl acetate and added to a separatory funnel containing 25 mL of a saturated
aqueous solution of NaCl. The layers were separated and the aqueous layer was extracted with
EtOAc (3
2 4
10 mL). The combined organic extracts were then dried with Na SO and
concentrated in vacuo. Purification of the crude product by flash chromatography (silica gel: 10%
to 100% ethyl acetate in hexanes) afforded the title compound as a yellow oil (181 mg, 0.63
–
1
1
mmol, 63%). IR (film) 3400, 2935, 2880, 2226, 1472, 1327, 1265, 1154, 1034, 1012 cm ; H
NMR (500 MHz, CDCl 7.53 (d, J = 8.3 Hz, 2H, PhH-4-CN), 7.41 (d, J = 8.2 Hz, 2H, PhH-4-
CN), 7.34 (d, J = 8.0 Hz, 1H, IndoleH), 7.27 (d, J = 8.2 Hz, 1H, IndoleH), 7.19 (t, J = 7.7 Hz, 1H,
3
)

Supplementary Material
S 18
IndoleH), 7.00 (t, J = 7.5 Hz, 1H, IndoleH), 6.93 (s, 1H, IndoleH), 4.47 (t, J = 7.7 Hz, 1H,
NMeIndole)CH(Ph-4-CN)), 3.76 (s, 3H, NMeIndole), 3.70-3.56 (m, 2H, CH OH), 2.44 (td, J =
3.7, 6.8 Hz, 1H, CH CH OH), 2.22 (td, J = 13.9, 6.2 Hz, 1H, CH CH OH); C NMR (125
(
2
13
1
2
2
2
2
MHz, CDCl
3
)
150.8, 137.3, 132.3, 128.7, 127.0, 126.1, 122.0, 119.2, 119.14, 119.11, 116.4,
+
1
09.9, 109.4, 60.8, 39.0, 38.2, 32.9; HRMS (ESI) exact mass calculated for [M+H] (C19
H
19
N
2
O)
requires m/z 291.1497, found m/z 291.1478.
Benzyl 1-(4-cyanophenyl)-3-hydroxypropylcarbamate. Prepared according to the general
2
procedure using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128
mg of terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv),
290 mg of benzyl (3-oxopropyl)carbamate (1.40 mmol, 1.4 equiv), 33 L of N-
isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L
of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU (31). After 53 h, the reaction
mixture was transferred to a 25 mL round-bottom flask and diluted with 8 mL of DCM and 2 mL
º
of MeOH. The reaction mixture was then cooled to 0 C and 189 mg of sodium borohydride (5.00
mmol, 5.00 equiv) was added to reduce the resulting aldehyde to the respective alcohol. The
reaction mixture was stirred for 30 min and then diluted with ethyl acetate and added to a
separatory funnel containing 25 mL of a saturated aqueous solution of NaCl. The layers were
separated and the aqueous layer was extracted with EtOAc (3 10 mL). The combined organic
2 4
extracts were then dried with Na SO and concentrated in vacuo. Purification of the crude product
by flash chromatography (silica gel: 10% to 20% acetonitrile in DCM) afforded the title
compound as a yellow oil (218 mg, 0.71 mmol, 71%). IR (film) 3327, 2952, 2229, 1693, 1518,
–
1 1
1
7
253, 1049 cm ; H NMR (500 MHz, CDCl
3
) 7.58 (d, J = 7.7 Hz, 2H, PhH-4-CN), 7.38 (d, J =
PhH), 5.98 (d, J = 5.8 Hz, 1H, NHCBz), 5.11–
.6 Hz, 2H, PhH-4-CN), 7.35–7.25 (m, 5H, OCH
2

Supplementary Material
S 19
4
.89 (m, 3H, OCH
2
Ph & NHCBzCH(Ph-4-CN)), 3.70–3.53 (m, 2H, CH
2
OH), 2.08–1.97 (m, 1H,
1
3
CH CH OH), 1.89–1.77 (m, 1H, CH
2
2
2
CH
2
OH); C NMR (125 MHz, CDCl
3
)
156.4, 147.8,
136.3, 132.6, 128.7, 128.4, 128.3, 127.3, 118.9, 111.2, 67.2, 59.1, 53.2, 38.1; HRMS (ESI) exact
+
mass calculated for [M+H] (C18
H
19
N
2
O
3
) requires m/z 311.1396, found m/z 311.1393.
4
-(2-Methyl-4-oxobutan-2-yl)benzonitrile. Prepared according to the general procedure using
2
6
.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 147 L
of isovaleraldehyde (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20
equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and
2.0 mL of DMPU. After 48 h, the reaction mixture was subjected to the workup protocol outlined
in the general procedure and purified by flash chromatography (silica gel: 10% to 100% ethyl
acetate in hexanes) to afford the title compound as a clear oil (138 mg, 0.74 mmol, 74%). IR
–
1
1
(
film) 2970, 2228, 1707, 1403, 1267, 1235, 1187, 1130, 1097, 837 cm ; H NMR (500 MHz,
CDCl 9.30 (t, J = 2.6 Hz, 1H, CHO), 7.40 (d, J = 8.5 Hz, 2H, ArH), 7.27 (d, J = 8.5 Hz, 2H,
ArH), 2.52 (d, J = 2.6 Hz, 2H, CH
3
)
1
3
2
3
CHO), 1.24 (s, 6H, (CH )C(Ph-4-CN)); C NMR (125 MHz,
CDCl
3
)
201.6, 153.1, 132.1, 126.6, 119.0, 110.2, 56.1, 37.3, 29.1; HRMS (ESI) exact mass
+
calculated for [M+H] (C12
H14NO) requires m/z 188.1075, found m/z 188.1077.

Supplementary Material
S 20
4
-(1-(2-Oxoethyl)cyclohexyl)benzonitrile. Prepared according to the general procedure using
2
6
.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of
terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 147 L
of isovaleraldehyde (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20
equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and
2.0 mL of DMPU. After 72 h, the reaction mixture was subjected to the workup protocol outlined
in the general procedure and purified by flash chromatography (silica gel: 10% to 100% ethyl
acetate in hexanes) to afford the title compound as a clear oil (160 mg, 0.70 mmol, 70%). IR
–
1
1
(
film) 2932, 2859, 2227, 1717, 1454, 1406, 1268, 1017, 834, 736 cm ; H NMR (500 MHz,
CDCl 9.36 (s, 1H, CHO), 7.63 (d, J = 8.3 Hz, 2H, ArH), 7.49 (d, J = 8.3 Hz, 2H, ArH), 2.60
d, J = 2.2 Hz, 2H, CH CHO), 2.18–2.06 (m, 2H, cycH), 1.81–1.69 (m, 2H, cycH), 1.62–1.50 (m,
3
)
(
2
1
3
2
1
H, cycH), 1.48–1.31 (m, 4H, cycH); C NMR (125 MHz, CDCl
3
)
201.7, 151.1, 132.5, 127.5,
+
18.7, 110.2, 55.2, 40.9, 36.2, 25.9, 21.9; HRMS (ESI) exact mass calculated for [M+H]
18NO) requires m/z 228.1388, found m/z 228.1389.
(
C
15
H
tert-Butyl 4-(4-cyanophenyl)-4-(2-oxoethyl)piperidine-1-carboxylate. Prepared according to
2
the general procedure using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01
equiv), 128 mg of terephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol,
5.00 equiv), 318 mg of tert-butyl 4-(2-oxoethyl)piperidine-1-carboxylate (1.40 mmol, 1.4 equiv),

Supplementary Material
S 21
3
3 L of N-isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00
equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 47 h, the
reaction mixture was subjected to the workup protocol outlined in the general procedure and
purified by flash chromatography (silica gel: 5% to 40% ethyl acetate in benzene) to afford the
title compound as a clear oil (232 mg, 0.71 mmol, 71%). IR (film) 2977, 2934, 2229, 1720, 1683,
–
1 1
1
420, 1244, 1162, 733 cm ; H NMR (500 MHz, CDCl
Hz, 2H, ArH), 7.47 (d, J = 8.4 Hz, 2H, ArH), 3.62–3.52 (m, 2H, CH
CH NBoc), 2.71 (d, J = 1.4 Hz, 2H, CH CHO), 2.23–2.12 (m, 2H, CH
H, CH CH NBoc), 1.41 (s, 9H, C(CH
3
)
9.39 (s, 1H, CHO), 7.65 (d, J = 8.4
2
NBoc), 3.28–3.19 (m, 2H,
2
2
2
CH
2
NBoc), 1.94–1.84 (m,
13
2
1
2
2
3
)
3
); C NMR (125 MHz, CDCl
3
)
200.6, 154.9, 149.3,
32.9, 127.7, 118.7, 110.7, 80.1, 59.4, 54.1, 39.4, 35.1, 28.6; HRMS (ESI) exact mass calculated
+
for [M+H] (C19
H
25
N
2
O
3
) requires m/z 329.1865, found m/z 329.1853.
2
-Methoxy-4-(1-oxooctan-3-yl)benzonitrile and 3-methoxy-4-(1-oxooctan-3-yl)benzonitrile.
Prepared according to the general procedure using 6.6 mg of tris[2-phenylpyridinato-
2
C ,N]iridium(III) (10.0 mol, 0.01 equiv), 158 mg of 2-methoxyterephthalonitrile (1.00 mmol,
1
.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 106 mg of sodium carbonate (1.00
mmol, 1.00 equiv), 219 L of octanal (1.40 mmol, 1.4 equiv), 33 L of N-isopropylbenzylamine
0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20
(
mmol, 0.20 equiv) and 2.0 mL of DMPU. After 48 h, the reaction mixture was subjected to the
1
workup protocol outlined in the general procedure. Analysis of the crude reaction mixture by H
3
NMR in CDCl determined that the regioisomer ratio was 3.7:1. The crude reaction mixture was
purified by flash chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) to afford 2-
methoxy-4-(1-oxooctan-3-yl)benzonitrile (148 mg, 0.58 mmol, 58% yield) and 3-methoxy-4-(1-
oxooctan-3-yl)benzonitrile (40 mg, 0.15 mmol, 15% yield) as colorless oils. 2-methoxy-4-(1-

Supplementary Material
S 22
-
oxooctan-3-yl)benzonitrile; IR (film) 2928, 2857, 2226, 1723, 1606, 1464, 1420, 1267, 1030 cm
1
1
;
H NMR (500 MHz, CDCl
.2, 7.9 Hz, 1H, ArH), 6.76 (s, 1H, ArH), 3.91 (s, 3H, OCH
.68 (m, 2H, CH CHO), 1.70–1.49 (m, 2H, CH(Ar)CH
(CH CH ), 0.86–0.73 (m, 3H, CH(Ar)CH (CH
3
)
9.66 (s, 1H, CHO), 7.47 (d, J = 7.9 Hz, 1H, ArH), 6.82 (dd, J =
), 3.24–3.15 (m, 1H, CH(Ar)), 2.78–
(CH CH ), 1.28–1.12 (m, 6H,
CH
1
2
3
2
2
2
)
3
3
1
3
CH(Ar)CH
2
2
)
3
3
2
2
)
3
3
); C NMR (125 MHz,
CDCl
3
) 200.9, 161.7, 152.2, 134.1, 119.7, 116.7, 111.1, 100.1, 56.2, 50.7, 40.7, 36.3, 31.8, 27.1,
+
2
2.5, 13.9; HRMS (ESI) exact mass calculated for [M+H] (C16
H22NO
2
) requires m/z 260.1651,
found m/z 260.1648. 3-methoxy-4-(1-oxooctan-3-yl)benzonitrile; IR (film) 2928, 2858, 2230,
–
1 1
1
721, 1502, 1463, 1407, 1262, 1034 cm ; H NMR (500 MHz, CDCl
CHO), 7.23–7.18 (m, 2H, ArH), 7.05 (s, 1H, ArH), 3.83 (s, 3H, OCH
CH(Ar)), 2.74–2.60 (m, 2H, CH CHO), 1.71–1.54 (m, 2H, CH(Ar)CH (CH
m, 6H, CH(Ar)CH (CH CH ), 0.89–0.74 (m, 3H, CH(Ar)CH (CH CH
MHz, CDCl
3
)
9.62 (t, J = 1.9 Hz, 1H,
), 3.67–3.57 (m, 1H,
CH ), 1.32–1.12
3
2
2
2
)
3
3
1
3
(
2
2
)
3
3
2
2
)
3
3
); C NMR (125
3
)
201.4, 157.4, 138.3, 128.8, 125.0, 118.7, 113.5, 110.7, 55.8, 49.1, 34.5, 33.1,
+
3
2
1.7, 27.0, 22.6, 14.1; HRMS (ESI) exact mass calculated for [M+H] (C16
H22NO
2
) requires m/z
60.1651, found m/z 260.1656.
2,5-Dimethyl-4-(1-oxooctan-3-yl)benzonitrile. Prepared according to the general procedure
2
using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 156 mg of 2,5-
dimethylterephthalonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv),
1
3
06 mg of sodium carbonate (1.00 mmol, 1.00 equiv), 219 L of octanal (1.40 mmol, 1.4 equiv),
3 L of N-isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00
equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 36 h, the
reaction mixture was subjected to the workup protocol outlined in the general procedure and
purified by flash chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) to afford the

Supplementary Material
S 23
title compound as a clear oil (201 mg, 0.78 mmol, 78%). IR (film) 2927, 2222, 1723, 1459, 1392,
–
1 1
1
266, 908, 729 cm ; H NMR (500 MHz, CDCl
s, 1H, ArH), 3.48–3.38 (m, 1H, CH(Ar)), 2.77–2.65 (m, 2H, CH
.32 (s, 3H, ArCH ), 1.66–1.42 (m, 2H, CH(Ar)CH (CH
CH(Ar)CH (CH CH ), 0.82–0.72 (t, J = 6.6 Hz, 3H, CH(Ar)CH
MHz, CDCl
3
)
9.62 (s, 1H, CHO), 7.33 (s, 1H, ArH), 7.02
CHO), 2.44 (s, 3H, ArCH ),
CH ), 1.29–1.10 (m, 6H,
(CH
(
2
3
2
3
2
2
)
3
3
13
2
2
)
3
3
2
2 3 3
) CH ); C NMR (125
3
)
201.0, 148.3, 139.9, 134.6, 134.2, 127.7, 118.5, 110.4, 50.4, 36.5, 34.5, 32.0,
+
2
7.0, 22.8, 20.4, 19.4, 14.2; HRMS (ESI) exact mass calculated for [M+H] (C17
H24NO) requires
m/z 258.1858, found m/z 258.1859.
2
-(1-Oxooctan-3-yl)benzonitrile. Prepared according to the general procedure using 6.6 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of 1,2-dicyanobenzene
(1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 123 mg NaOAc (1.50
mmol, 1.50 equiv), 468 L of octanal (3.00 mmol, 3.0 equiv), 47.9 L of N-tert-
butylmethylamine (0.400 mmol, 0.40 equiv), 90 L of water (5.00 mmol, 5.00 equiv), 11 L of
acetic acid (0.20 mmol, 0.20 equiv) and 5.0 mL of DMSO. After 48 h, the reaction mixture was
diluted with DCM (50 mL) and added to a separatory funnel containing 30 mL of a 1 M aqueous
solution of NaOH. The layers were separated and the aqueous layer was extracted with DCM (20
2 4
mL). The combined organic extracts were washed with brine (40 mL), dried over Na SO ,
filtered, and concentrated in vacuo to afford the crude mixture. The crude material was purified
by flash chromatography (silica gel: 5% to 15% ethyl acetate in hexanes) to afford the title
compound as a light yellow oil (128.8 mg, 0.562 mmol, 56%). IR (film) 2929, 2224, 1722, 1485,
–
1 1
1
448, 1165, 1109, 763 cm ; H NMR (500 MHz, CDCl
3
)
9.70 (t, J = 1.6 Hz, 1H, CHO), 7.65
(d, J = 8.0 Hz, 1H, ArH), 7.57 (t, J = 7.8 Hz, 1H, ArH), 7.35–7.30 (m, 2H, ArH), 3.73–3.64 (m,
1
1
H, CH(Ar)), 2.89–2.7 8 (m, 2H, CH
2
CHO), 1.78–1.64 (m, 2H, CH(Ar)CH
2
(CH
2 3 3
) CH ), 1.33–
13
.05 (m, 6H, CH(Ar)CH (CH CH
2
2
)
3
3
), 0.89–0.77 (m, 3H, (CH
2
)
3
CH
3
); C NMR (125 MHz,

Supplementary Material
S 24
CDCl
3
) 200.4, 147.7, 133.2, 133.1, 127.3, 127.0, 118.1, 112.6, 49.7, 38.0, 36.0, 31.6, 26.8, 22.4,
+
1
4.0; HRMS (ESI) exact mass calculated for [M+H] (C15
H20NO) requires m/z 230.1545, found
m/z 230.1546.
5
-(1-Hydroxyoctan-3-yl)isobenzofuran-1(3H)-one. Prepared according to the general procedure
2
using 6.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 159 mg of 5-
cyanophthalide (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 82.0 mg
NaOAc (1.00 mmol, 1.00 equiv), 468 L of octanal (3.00 mmol, 3.0 equiv), 66.9 L of N-
isopropylbenzylamine (0.400 mmol, 0.40 equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L
of acetic acid (0.20 mmol, 0.20 equiv) and 4.0 mL of DMSO. After 23 h, the reaction mixture
was transferred to a 20 mL scintillation vial and diluted with 4 mL of DCM and 4 mL of EtOH.
The reaction mixture was then cooled to 0 ºC and 114 mg of sodium borohydride (3.00 mmol, 3.0
equiv) was added to reduce the resulting aldehyde to the respective alcohol. The reaction mixture
was stirred for 15 min, warmed to room temperature for a further 30 min, and quenched with
4
saturated aqueous NH Cl. The reaction mixture was then diluted with EtOAc and added to a
separatory funnel containing 25 mL of water. The layers were separated and the aqueous layer
was extracted with EtOAc (1 25 mL). The combined organic extracts were then washed with
2 4
brine, dried with Na SO and concentrated in vacuo. Purification of the crude product by flash
chromatography (silica gel: 20% to 45% ethyl acetate in hexanes) to afford the title compound as
a colorless oil (164.4 mg, 0.627 mmol, 63%). IR (film) 3415, 2928, 1745, 1455, 1346, 1042, 778,
–
1 1
7
00 cm ; H NMR (500 MHz, CDCl
3
)
7.85 (d, J = 7.9 Hz, 1H, ArH), 7.36 (d, J = 7.9 Hz, 1H,
O), 3.59–3.52 (m, 1H, CH OH), 3.47–3.39 (m, 1H,
OH), 2.93–2.85 (m, 1H, CH(Ar)), 2.06-1.96 (m, 1H, CH CH OH), 1.87–1.77 (m, 1H,
CH OH), 1.75–1.56 (m, 2H, CH(Ar)CH (CH CH ), 1.30 (br s, 1H, OH), 1.27–1.03 (m, 6H,
ArH), 7.30 (s, 1H, ArH), 5.31 (s, 2H, ArCH
2
2
CH
2
2
2
2
CH
2
2
2
)
3
3

Supplementary Material
CH(Ar)CH (CH CH
S 25
13
2
2
)
3
3
), 0.86–0.79 (m, 3H, (CH
2
)
3
CH
3
); C NMR (125 MHz, CDCl
3
)
171.1,
152.9, 147.1, 128.7, 125.8, 123.9 121.2, 69.5, 60.6, 42.7, 39.4, 36.7, 31.7, 27.2, 22.5, 14.0;
+
HRMS (ESI) exact mass calculated for [M+H] (C16
H
23
O
3
) requires m/z 263.1647, found m/z
2
63.1643.
3
-(4-(Phenylsulfonyl)phenyl)octanal. Prepared according to the general procedure using 6.6 mg
2
of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0
mol, 0.01 equiv), 243 mg of 4-
(phenylsulfonyl)benzonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00
equiv), 82.0 mg NaOAc (1.00 mmol, 1.00 equiv), 468 L of octanal (3.00 mmol, 3.0 equiv), 50.1
L of N-isopropylbenzylamine (0.300 mmol, 0.30 equiv), 90 L of water (5.00 mmol, 5.00
equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 4.0 mL of DMSO (32). After 20 h, the
reaction mixture was diluted with DCM (50 mL) and added to a separatory funnel containing 30
mL of a 1 M aqueous solution of NaOH. The layers were separated and the aqueous layer was
extracted with DCM (20 mL). The combined organic extracts were washed with brine (40 mL),
2 4
dried over Na SO , filtered, and concentrated in vacuo to afford the crude mixture. The crude
material was purified by flash chromatography (silica gel: 0% to 0.75% ethyl acetate in DCM) to
afford the title compound as a colorless oil (238.4 mg, 0.691 mmol, 69%). IR (film) 2927, 1721,
–
1 1
1
447, 1306, 1153, 1105, 833, 687 cm ; H NMR (500 MHz, CDCl
CHO), 7.95 (d, J = 7.1 Hz, 2H, PhH), 7.87 (d, J = 8.4 Hz, 2H, SO ArH), 7.58 (t, J = 7.3 Hz, 1H,
PhH), 7.52 (dd, J = 7.3, 7.1 Hz, 2H, PhH), 7.33 (d, J = 8.4 Hz, 2H, SO ArH), 3.29–3.21 (m, 1H,
CH(Ar)), 2.79–2.68 (m, 2H, CH CHO), 1.68–1.52 (m, 2H, CH(Ar)CH (CH CH ), 1.28–1.02
m, 6H, CH(Ar)CH (CH CH ), 0.85-0.77 (m, 3H, (CH ); C NMR (125 MHz, CDCl
00.7, 150.2, 141.5, 139.6, 133.1, 129.3, 128.4, 128.0, 127.6, 50.2, 39.6, 36.2, 31.5, 26.8, 22.4,
3
)
9.64 (t, J = 1.6 Hz, 1H,
2
2
2
2
2
)
3
3
13
(
2
2
)
3
3
2
)
3
CH
3
3
)
2
1
+
25 3
4.0; HRMS (ESI) exact mass calculated for [M+H] (C20H O S) requires m/z 345.1524, found

Supplementary Material
S 26
m/z 345.1520.
3
-(Pyridin-4-yl)octanal. Prepared according to the general procedure using 6.6 mg of tris[2-
2
phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 104 mg of isonicotinonitrile (1.00
mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 219 L of octanal (1.40 mmol,
1.4 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00
mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 38
h, the reaction mixture was subjected to the workup protocol outlined in the general procedure
and purified by flash chromatography (silica gel: 25% to 100% ethyl acetate in hexanes) to afford
the title compound as a yellow oil (144 mg, 0.70 mmol, 70%). IR (film) 2928, 2858, 1722, 1599,
–
1 1
1
415, 993, 820 cm ; H NMR (500 MHz, CDCl
3
)
9.61 (s, 1H, CHO), 8.44 (d, J = 4.8 Hz, 2H,
CHO),
2 2 3 3 2 2 3 3
(CH ) CH ), 1.22–1.07 (m, 6H, CH(Ar)CH (CH ) CH ), 0.81–
ArH), 7.07 (d, J = 5.1 Hz, 2H, ArH), 3.17–3.05 (m, 1H, CHAr), 2.77–2.61 (m, 2H, CH
2
1
0
5
.66–1.45 (m, 2H, CH(Ar)CH
.70 (m, 3H, CH(Ar)CH (CH
13
2
2
)
3
CH
3
); C NMR (125 MHz, CDCl
3
)
200.7, 153.6, 150.0, 123.1,
+
0.0, 39.2, 35.8, 31.8, 27.0, 22.5, 14.1; HRMS (ESI) exact mass calculated for [M+H]
20NO) requires m/z 206.1545, found m/z 206.1563.
(
C
13
H

Supplementary Material
S 27
3
-(2-Methylpyridin-4-yl)octanal. Prepared according to the general procedure using 5.3 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (8.00
methylisonicotinonitrile (0.80 mmol, 1.00 equiv), 449 mg of DABCO (4.00 mmol, 5.00 equiv),
75 L of octanal (1.12 mmol, 1.4 equiv), 27 L of N-isopropylbenzylamine (0.16 mmol, 0.20
equiv), 43 L of water (2.40 mmol, 3.00 equiv), 9 L of acetic acid (0.16 mmol, 0.20 equiv) and
.6 mL of DMPU. After 48 h, the reaction mixture was subjected to the workup protocol outlined
mol, 0.01 equiv), 95 mg of 2-
1
1
in the general procedure and purified by flash chromatography (silica gel: 25% to 100% ethyl
acetate in hexanes) to afford the title compound as a yellow oil (119 mg, 0.54 mmol, 68%). IR
–
1 1
(
film) 2956, 2857, 2927, 1722, 1598, 1415, 1069, 993, 819 cm ; H NMR (500 MHz, CDCl
.64 (t, J = 1.5 Hz, 1H, CHO), 8.35 (d, J = 5 Hz, 1H, ArH), 6.95 (s, 1H, ArH), 6.90 (d, J = 4.80
Hz, 1H, ArH), 3.14–3.04 (m, 1H, CHAr), 2.74–2.66 (m, 2H, CH CHO), 2.50 (s, 3H, ArCH ),
), 1.27–1.10 (m, 6H, CH(Ar)CH (CH CH ), 0.84–
); C NMR (125 MHz, CDCl 201.1, 158.9, 153.7, 149.2,
3
)
9
2
3
1
0
1
.67–1.47 (m, 2H, CH(Ar)CH
2
(CH
2
)
3
CH
3
2
2
)
3
3
13
.75 (m, 3H, CH(Ar)CH (CH
2
2
)
3
CH
3
3
)
22.7, 120.2, 50.1, 39.1, 36.1, 31.8, 26.9, 24.5, 22.5, 14.4; HRMS (ESI) exact mass calculated for
+
[
M+H] (C14
H22NO) requires m/z 220.1701, found m/z 220.1705.
3
-(3-Chloropyridin-4-yl)octanal. Prepared according to the general procedure using 6.6 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (10.0
mol, 0.01 equiv), 139 mg of 3-
chloroisonicotinonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv),
1
3
06 mg of sodium carbonate (1.00 mmol, 1.00 equiv), 219 L of octanal (1.40 mmol, 1.4 equiv),
3 L of N-isopropylbenzylamine (0.20 mmol, 0.20 equiv), 54 L of water (3.00 mmol, 3.00
equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After 26 h, the
reaction mixture was subjected to the workup protocol outlined in the general procedure and
purified by flash chromatography (silica gel: 10% to 75% ethyl acetate in hexanes) to afford the
title compound as a yellow oil (130 mg, 0.54 mmol, 54%). IR (film) 2928, 2858, 1723, 1585,

Supplementary Material
467, 1400, 1096, 1033, 833, 731 cm ; H NMR (500 MHz, CDCl
S 28
–
1 1
1
3
)
9.67 (s, 1H, CHO), 8.53
(
s, 1H, ArH), 8.39 (d, J = 5.0 Hz, 1H, ArH), 7.11 (d, J = 5.0 Hz, 1H, ArH), 3.80–3.65 (m, 1H,
CHAr), 2.83–2.64 (m, 2H, CH CHO), 1.68–1.58 (m, 2H, CH(Ar)CH (CH CH ), 1.29–1.15 (m,
H, CH(Ar)CH (CH CH ), 0.87–0.74 (m, 3H, CH(Ar)CH (CH CH ); C NMR (125 MHz,
2
2
2
)
3
3
13
6
2
2
)
3
3
2
2
)
3
3
CDCl
3
) 200.4, 154.5, 150.5, 149.8, 133.9, 128.3, 49.0, 35.5, 34.8, 31.8, 26.8, 22.6, 13.9; HRMS
+
(
ESI) exact mass calculated for [M+H] (C13
H19ClNO) requires m/z 240.1155, found m/z
240.1152.
3
-(1H-Pyrrolo[2,3-b]pyridin-4-yl)octan-1-ol. Prepared according to the general procedure using
2
6
.6 mg of tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 143.1 mg of 7-
azaindole-4-carbonitrile (1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv),
23 mg NaOAc (1.50 mmol, 1.5 equiv), 468 L of octanal (3.00 mmol, 3.0 equiv), 66.9 L of N-
1
isopropylbenzylamine (0.400 mmol, 0.40 equiv), 90 L of water (5.00 mmol, 5.0 equiv), 11 L
of acetic acid (0.200 mmol, 0.20 equiv) and 4.0 mL of DMSO. After 48 h, the reaction mixture
was transferred to a 20 mL scintillation vial and diluted with 4 mL of DCM and 4 mL of EtOH.
The reaction mixture was then cooled to 0 ºC and 114 mg of sodium borohydride (3.00 mmol, 3.0
equiv) was added to reduce the resulting aldehyde to the respective alcohol. The reaction mixture
was stirred for 20 min, warmed to room temperature for a further 40 min, and quenched with
4
saturated aqueous NH Cl. The reaction mixture was then diluted with EtOAc and added to a
separatory funnel containing 25 mL of water. The layers were separated and the aqueous layer
was extracted with EtOAc (1 25 mL). The combined organic extracts were then washed with
2 4
brine, dried with Na SO , and concentrated in vacuo. Purification of the crude product by flash
chromatography (silica gel: 50% to 100% ethyl acetate in hexanes) to afford the title compound
–
as a light yellow oil (130 mg, 0.53 mmol, 53%). IR (film) 3158, 2927, 1592, 1340, 1051, 726 cm
1
1
;
3
H NMR (500 MHz, CDCl ) 10.68 (br s, 1H, NH), 8.24 (d, J = 5.0 Hz, 1H, ArH), 7.32 (d, J =

Supplementary Material
S 29
3
1
.5 Hz, 1H, ArH), 6.92 (d, J = 5.0 Hz, 1H, ArH), 6.58 (d, J = 3.5 Hz, 1H, ArH), 3.57–3.50 (m,
H, CH OH), 3.47–3.41 (m, 1H, CH OH), 3.23–3.15 (m, 1H, CH(Ar)), 2.13–1.96 (m, 2H,
CH OH), 1.88 (br s, 1H, OH), 1.83–1.71 (m, 2H, CH(Ar)CH (CH CH ), 1.27–1.05 (m,
H, CH(Ar)CH ); C NMR (125 MHz, CDCl
2
2
CH
2
2
2
2
)
3
3
13
6
1
2
(CH
2
)
3
CH
3
), 0.85–0.77 (m, 3H, (CH
2
)
3
CH
3
3
)
48.6, 147.6, 142.8, 124.3, 120.1, 113.9, 99.3, 60.9, 39.7, 38.6, 35.9, 31.8, 27.3, 22.5, 14.0;
+
HRMS (ESI) exact mass calculated for [M+H] (C16
H
23
O
3
) requires m/z 247.1810, found m/z
247.1803.
4
-(3-Oxopropyl)benzonitrile. Prepared according to the general procedure using 6.6 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of terephthalonitrile
(1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 220 L of
propionaldehyde (1.40 mmol, 3.0 equiv), 33 L of N-isopropylbenzylamine (0.20 mmol, 0.20
equiv), 54 L of water (3.00 mmol, 3.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and
2.0 mL of DMPU. After 24 h, the reaction mixture was diluted with DCM (40 mL) and added to a
separatory funnel containing 25 mL of a 1 M aqueous solution of NaOH. The layers were
separated and the aqueous layer was extracted with DCM (2 10 mL). The combined organic
2 4
extracts were washed with brine (40 mL), dried over Na SO , filtered, and concentrated in vacuo
to afford a yellow liquid containing the product as a 4:1 mixture of aldehyde and cyanohydrin, as
1
determined by H NMR analysis of the crude mixture. Purification of the crude product by flash
chromatography (silica gel: 10% to 75% ethyl acetate in hexanes) afforded a pure mixture of the
-
aryl aldehyde and cyanohydrin product. This mixture was placed under high vacuum for 8 h to
afford the desired aldehyde as a colorless oil (124 mg, 0.78 mmol, 78% yield). The spectral data
matched that reported in the literature (33).

Supplementary Material
S 30
General Procedure for the Racemic -Arylation of Ketones: An oven-dried 8 mL vial
equipped with a Teflon septum and magnetic stir bar was charged with tris[2-phenylpyridinato-
2
C ,N]iridium(III) (10.0 mol, 0.01 equiv), the corresponding aromatic nitrile (1.00 mmol, 1.0
equiv), azepane (0.20 mmol, 0.20 equiv), and 1,4-diazabicyclo[2.2.2]octane (5.00 mmol, 5.0
equiv). The vial was purged with a stream of nitrogen and 2.0 mL of DMPU was added via
syringe, followed by the corresponding ketone (5.00 mmol, 5.0 equiv), acetic acid (0.20 mmol,
0.20 equiv), and water (3.00 mmol, 3.00 equiv). The reaction mixture was then cooled to –78 ºC
and degassed via vacuum evacuation (5 min), backfilled with nitrogen, and warmed to room
temperature. This process was repeated three times. After the reaction was thoroughly degassed,
the vial was placed approximately 2 cm from a 26 W fluorescent lamp. After the indicated time
period, the reaction mixture was diluted with ethyl acetate and added to a separatory funnel
containing 25 mL of a saturated solution of NaCl. The layers were separated and the aqueous
layer was extracted with EtOAc (3 10 mL). The combined organic extracts were dried over
2 4
Na SO and concentrated in vacuo. Purification of the crude product by flash chromatography on
silica gel using the indicated solvent system afforded the desired -arylated ketone product.
4
-(3-Oxocyclohexyl)benzonitrile. Prepared according to the general procedure using 6.6 mg of
2
tris[2-phenylpyridinato-C ,N]iridium(III) (10.0 mol, 0.01 equiv), 128 mg of terephthalonitrile
(1.00 mmol, 1.00 equiv), 561 mg of DABCO (5.00 mmol, 5.00 equiv), 24.0 L of azepane (0.20
mmol, 0.20 equiv), 1517 L of cyclohexanone (5.00 mmol, 5.00 equiv), 360 L of water (20.00
mmol, 20.00 equiv), 11 L of acetic acid (0.20 mmol, 0.20 equiv) and 2.0 mL of DMPU. After
9
8 h, the reaction mixture was subjected to the workup protocol outlined in the general procedure
and purified by flash chromatography (silica gel: 10% to 100% ethyl acetate in hexanes) to afford