A concise synthesis of ortho-iodobenzyl alcohols via addition of ortho-Iodophenyl grignard reagent to aldehydes and ketones

Article abstract of DOI:10.1055/s-0029-1217406

A wide range of both secondary and tertiary ortho-iodobenzyl alcohols was synthesized via addition of ortho-iodophenyl Grignard reagents to aldehydes and ketones. Significant improvements in terms of yields were observed with ketones upon addition of CeCl3. The potential application of the target compounds as precursors for novel electrophilic trifluoromethylating reagents based on hypervalent iodine derivatives was demonstrated. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217406

2818
PRACTICAL SYNTHETIC PROCEDURES
A Concise Synthesis of ortho-Iodobenzyl Alcohols via Addition of
ortho-Iodophenyl Grignard Reagent to Aldehydes and Ketones
A
C
oncise
á
S
ynthesis
n
of ortho-Iodobenzy
C
l
A
lcohols vengroš, Daniel Stolz, Antonio Togni*
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, ETH Zurich,
Wolfgang-Pauli-Str. 10, 8093 Zurich, Switzerland
Fax +41(44)6321310; E-mail: togni@inorg.chem.ethz.ch
PSP
Received 21 April 2009; revised 6 May 2009
No167
Abstract: A wide range of both secondary and tertiary ortho-iodobenzyl alcohols was synthesized via addition of ortho-iodophenyl
Grignard reagents to aldehydes and ketones. Significant improvements in terms of yields were observed with ketones upon addition of
CeCl3. The potential application of the target compounds as precursors for novel electrophilic trifluoromethylating reagents based on hyper-
valent iodine derivatives was demonstrated.
Key words: addition reactions, Grignard reactions, organometallic reagents, benzyl alcohols, hypervalent iodine compounds
I
I
1
2 M i-PrMgCl (1 equiv)
–30 °C to –20 °C, 20 min
0.3 M in anhyd THF
O
OH
I
(0.67 equiv)
CeCl3 (1 equiv)
– 78 °C to –10 °C, 2 h
THF
OH
I
R1
R2
R–CHO (0.83 equiv)
3
CeCl2
I
MgX
I
R1
R2
6
R
– 78 °C to 25 °C, 15 h
THF
–20 °C to 25 °C, 15 h
THF
7
2
4
5
53–87% yields
6 examples
59–97% yields
8 examples
Scheme 1
Aryl iodides frequently appear in chemical synthesis as suppliers at a significantly lower price or promptly syn-
target compounds or remarkably versatile intermediates. thesized from cheap and readily available starting materi-
Especially the latter role places these compounds in the als. Thus, anthranilic acid (8) undergoes diazotation upon
unique position to be transformed into a plethora of im- treatment with isoamyl nitrite in the presence of trichloro-
portant products, usually by transition-metal-catalyzed acetic acid.6 The resulting benzenediazonium-2-carboxy-
coupling reactions1 or via the corresponding organolithi- late (9) then forms benzyne, which is rapidly intercepted
um or organomagnesium species.2 Due to our interest in by iodine to afford 1 in satisfactory yield of 60%
the chemistry of hypervalent iodine compounds,3 we (Scheme 2).
needed a concise and efficient access to ortho-iodobenzyl
alcohol derivatives. Though a broad palette of established
protocols installing the iodine atom at the aromatic system
is available,4 only a few of them are concerned with the io-
dination at the ortho-position.5 We felt intrigued by an al-
ternative approach, which would rely upon modification
of an aromatic system in the position ortho to iodine and
considered 1,2-diiodobenzene (1) as a potential ortho-
iodophenyl surrogate. Although one may argue that 1 is a
rather expensive reagent, it can be purchased from bulk
ONO
–
CO2
CO2H
NH2
I2, DCE
Cl3CCOOH
THF, r.t., 90 min
1
N+2
84 °C, 10 min
8
9
60%
Scheme 2 Facile synthesis of 1,2-diiodobenzene (1)
Selective replacement of one iodine atom in 1,2-diiodo-
benzene by transition-metal-catalyzed cross-coupling has
already been described,7 also the formation of the corre-
sponding 2-iodophenylmagnesium species 2, however,
without systematic study of its reactivity.8 As the reaction
SYNTHESIS 2009, No. 16, pp 2818–2824
x
x.
x
x
.
2
0
0
9
Advanced online publication: 22.06.2009
DOI: 10.1055/s-0029-1217406; Art ID: Z07809SS
© Georg Thieme Verlag Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Concise Synthesis of ortho-Iodobenzyl Alcohols
Table 1 Reactivity of 2 with Various Aldehydes
2819
of 2 with carbonyl compounds would directly afford the
desired ortho-iodobenzyl alcohols, we set out to inspect
the reactivity of 2 with various electrophiles.
Substrate
Product
Yield (%)
OH
I
Although the use of 2-iodophenylmagnesium species 2 is
described in the literature,9 its detailed and reproducible
preparation is not. We thus primarily focused our atten-
tion on establishing conditions under which 2 is formed in
an efficient and reliable manner. Extensive experimenta-
tion revealed that when 2 mmol of a 0.3 M solution of
diiodobenzene (1) in anhydrous THF was treated with 1 mL
of a 2 M solution of isopropylmagnesium chloride at –30 °C
and the resulting mixture was gradually warmed to –20 °C
over a period of 20 minutes, species 2 was quantitatively
formed. Thus, GC-MS analysis of hydrolyzed samples of
such mixtures showed the presence of iodobenzene exclu-
sively (Figure 1).
CHO
89
79
3a
4a
OH
I
CHO
MeO
MeO
OMe
CHO
OMe
OH
3b
4b
Cl
Cl
I
94
97
3c
4c
OH
I
Br
CHO
Br
3d
4d
I
CHO
N
94
N
CPh3
OH
CPh3
3e
4e
4f
Figure 1 Formation of 2-iodophenylmagnesium halide and GC
traces of the hydrolyzed reaction mixture
OH
I
CHO
78
59
We then proceeded to study the reactivity of 2 with vari- 3f
ous electrophiles (Scheme 1). A broad palette of both
electron-rich and electron-poor aromatic and aliphatic al-
dehydes were tested and the reaction proved efficient
yielding the anticipated ortho-iodobenzyl alcohols bear-
OH
I
CHO
Br
Br
ing a variety of functional groups (Table 1).
3g
4g
It is important to note that some of these compounds could
not be prepared by ortho-directing lithiation followed by
quenching with iodine because of the incompatibility of
some substituents with the reaction conditions of the lithi-
ation process (e.g., substrates 3d and 3g). Also the two
O
OH
I
O
CHO
71
3h
4h
methoxy groups in 3,4-dimethoxybenzaldehyde (3b)
would direct the metalation to occur ortho to a methoxy
group,10 thus rendering our desired product 4b inaccessi-
ble. Interestingly, when 3-acetoxybenzaldehyde (3h) was
exposed to 2, the reaction took place exclusively at the al-
dehyde functionality leaving the ketone moiety intact. The
lower yield might be explained by the formation of by-
products resulting from aldol condensation.
tion of 2 with anhydrous CeCl3,11 led to significantly
increased yields of the desired 2-iodobenzyl alcohols
(Scheme 1, Table 2).
It is noteworthy that with some substrates 5 was prone to
react even if 2 proved completely unreactive (ketone 6b).
A broad palette of various a,a-disubstituted ortho-iodo-
benzyl alcohols thus became accessible. To underline the
synthetic utility of our strategy, note that the 2-iodobenzyl
alcohol 7g can also be synthesized from expensive, com-
mercially available hexafluorocumyl alcohol via ortho-
lithiation followed by the reaction with iodine in only
65% yield, whereby the purification of the product is rath-
er troublesome.5b In our hands, 7g was formed in 80%
yield with two equivalents of hexafluoroacetone (6g), but
We subsequently sought to expand our protocol to other
electrophiles. Preliminary results showed that ketones re-
acted only sluggishly and in the case of sterically hindered
ones, the addition of 2 did not occur at all (Table 2). We
considered the use of more nucleophilic analogues of 2
and were delighted to witness that the use of correspond-
ing organocerium species 5, prepared by the transmetala-
Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York

2820
J. Cvengroš et al.
PRACTICAL SYNTHETIC PROCEDURES
imines gave complex reaction mixtures of a negligible
synthetic value. Only acetic anhydride readily reacted
with 5 to afford the anticipated 1-(2-iodophenyl)ethanone
(7h) in 82% yield.
Table 2 Comparison of the Reactivity of 2 or 5 with Various Ke-
tones
Substrate
Product
Yield (%)
with 2 with 5
To demonstrate the synthetic potential of the target com-
pounds, we chose the bistrifluoromethylated 2-iodoben-
zyl alcohol 7g and submitted it to oxidative cyclization
with t-BuOCl (Scheme 3). Thus, the resulting 1-chloro-
benziodoxole 10 was obtained in 90% yield over two
steps, this being a significant improvement compared to
previous efforts.3a,12 Intermediate 10 was then treated with
potassium acetate to smoothly afford the acetate 11. Sub-
sequent substitution of the acetoxy group by the action of
Ruppert’s reagent (TMSCF3) in the presence of cesium
fluoride furnished the I–CF3 l3-iodane 12. The entire syn-
thesis starting from diiodobenzene proved highly efficient
as 12 was obtained in only 4 steps with an overall yield of
53%, while the original preparation afforded 31% from
hexafluorocumyl alcohol.
O
OH
I
<10
53
87
7a
6a
OH
I
O
a
–
N
N
Bn
Bn
6b
7b
O
OH
I
22
64
66
72
6c
7c
OH
I
F3C
I
O
R
I
O
O
CF3
CF3
Ph
CF3
CF3
TMSCF3, CsF
t-BuOCl
Ph
7g
MeCN
65%
CH2Cl2
94%
6d
7d
7e
12
R = Cl 10
R = OAc 11
AgOAc, MeCN
97%
OH
I
44
53
O
Scheme 3 Synthesis of electrophilic trifluoromethylating reagent
12
6e
I
OH
In conclusion, we have presented a concise approach to-
wards a wide range of ortho-iodobenzyl alcohols by an
addition of organomagnesium 2 or organocerium species
5 to aldehydes and ketones, respectively. The methodolo-
gy was applied to a broad spectrum of substrates affording
synthetically useful products, the preparation of which
could be troublesome or impossible by other methods. In
line with our research activities, one of the tertiary ortho-
iodobenzyl alcohols 7g was used in the synthesis of the
known hypervalent trifluoromethyl iodine compound 12
in a significantly improved yield compared to that previ-
ously reported.
a
a
–
–
O
7f
6f
OH
I
O
80b
(96)c
F3C
–
F3C
F3C
CF3
6g
7g
I
O
O
O
33
82
O
6h
7h
All manipulations were performed under argon using standard
Schlenk techniques, unless otherwise stated. 1H, 19F, and 13C NMR
spectra were recorded on Bruker Avance spectrometers AC 200,
a No product detected.
b 2 equiv of hexafluoroacetone were used.
c Hexafluoroacetone was introduced directly into the reaction mixture
in large excess.
1
DPX 250, and DPX 300. H positive chemical shifts in ppm are
downfield from TMS. 19F NMR spectra were referenced to external
CFCl3. Mass spectra were measured by the MS service of the Lab-
oratorium für Organische Chemie (ETH Zürich). IR spectra were
recorded on PerkinElmer Spectrum BX spectrometer.
the yield could be increased to 96% upon bubbling 6g
through the reaction mixture. Unfortunately, in the case of
camphor (6f) the reaction failed completely in both cases.
We suspect that the steric hindrance around the carbonyl
functionality in camphor is too important for the rather
bulky 2-iodophenyl organometallic species 2 or 5.
Diiodobenzene (1)
Anthranilic acid (8; 5 g, 36.4 mmol) and trichloroacetic acid (45 mg,
0.28 mmol, 0.7 mol%) were dissolved in THF (35 mL) in a beaker
and the solution was cooled down to 0 °C. Isoamyl nitrite (8.1 mL,
59.8 mmol, 1.64 equiv) was added dropwise and the resulting mix-
ture was maintained at 18–25 °C and magnetically stirred for 2 h. A
pale brown precipitate was formed. Benzenediazonium carboxylate
is reported to detonate violently upon scratching or heating.6 All
Further attempts to react 2 or 5 with other electrophiles
proved less fruitful as esters were left intact and nitriles or
Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Concise Synthesis of ortho-Iodobenzyl Alcohols
2821
necessary security measures should be taken and the compound
should be constantly kept wet with solvent. It was filtered on a plas-
tic funnel equipped with a glass frit and washed with THF (3 × 50
mL) and subsequently with 1,2-dichloroethane (3 × 50 mL). The
precipitate was then transferred with the aid of a plastic spoon and
1,2-dichloroethane (50 mL) to a beaker. The resultant slurry was
then carefully (!) added via pipette to a gently boiling solution of I2
(18.5 g, 72.8 mmol, 2 equiv) in 1,2-dichloroethane (175 mL). The
resulting solution was then refluxed for 2 h until the frothing ceased.
It was cooled down to r.t., aq sat. Na2S2O3 (100 mL) was added, and
the mixture was stirred for 15 min. The aqueous phase was then ex-
tracted with CH2Cl2 (3 × 100 mL). The combined organic layers
were dried (MgSO4) and concentrated. Flash chromatography (sili-
ca gel, hexane) and distillation yielded 1,2-diiodobenzene as a col-
orless oil (7.1 g, 60%); bp 64–65 °C/0.059 mbar.
1H NMR (300 MHz, CDCl3): d = 2.73 (s, 1 H, OH), 6.07 (s, 1 H,
CHOH), 7.01 (dt, 3J = 7.5 Hz, J = 1.5 Hz, 1 H, ArH), 7.28–7.45 (m,
6 H, ArH), 7.55 (dd, J = 7.8, 1.8 Hz, 1 H, ArH), 7.87 (dd, J = 0.9,
7.8 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 79.0 (COH), 98.8 (CI), 127.3,
127.8, 128.4, 128.5, 128.6, 129.5, 139.6, 142.2, 145.4.
HRMS (EI): m/z [M]+ calcd for C13H11IO: 309.9855 (100.0%),
310.9888 (14.1%); found: 309.9850 (100.0%), 310.9887 (13.9%).
(3,4-Dimethoxyphenyl)(2-iodophenyl)methanol (4b)
Starting from 3b (100 mg, 0.6 mmol), 4b was synthesized according
to GP1. Column chromatography (hexane–EtOAc, 3:1) gave a col-
orless oil (175 mg, C15H15IO3, M = 370.18 g/mol, 79%).
IR (neat): 3476, 3000, 2932, 2833, 1592, 1561, 1512, 1460, 1436,
1416, 1254, 1232, 1185, 1024, 1006, 912, 858, 806, 781, 742, 670,
635 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.05 (ddd, 3J = 6 Hz, 4J = 3.6 Hz,
5J = 0.6 Hz), 7.90 (ddd, 3J = 6 Hz, 4J = 3.6 Hz, 5J = 0.6 Hz).
3
1H NMR (300 MHz, CDCl3): d = 2.98 (d, J = 3.0 Hz, 1 H, OH),
13C NMR (75 MHz, CDCl3): d = 108.0 (CI), 129.2, 139.5.
3
3.81, 3.82 (2 s, 2 × 3 H, 2 × OCH3), 5.94 (d, J = 2.7 Hz, 1 H,
CHOH), 6.78 (d, 3J = 8.4 Hz, ArH), 6.86 (dd, 4J = 1.8 Hz, 3J = 8.4
Hz, ArH), 6.96 (m, 2 H, ArH), 7.35 (t, 3J = 7.2 Hz, 1 H, ArH), 7.53
(dd, 4J = 1.5 Hz, 3J = 7.8 Hz, 1 H, ArH), 7.81 (d, 3J = 7.8 Hz, 1 H,
ArH).
Addition of ortho-Iodophenylmagnesium Species 2 to Alde-
hydes; General Procedure 1
The Grignard reagent was prepared immediately before use. In a
Schlenk flask, 1,2-diiodobenzene (660 mg, 2 mmol) was dissolved
in anhyd THF (6 mL) under argon. After cooling to –30 °C, isopro-
pylmagnesium chloride (2.0 M solution in THF, 1 mL) was added
dropwise and the resulting orange colored mixture was warmed to
–20 °C over a period of 20 min. The reaction was monitored by GC-
MS. A solution of aldehyde 3 (1.67 mmol) in THF (2 mL) was add-
ed at –20 °C and the mixture was allowed to warm up to r.t. over-
night. After dilution with Et2O (10 mL), the mixture was
hydrolyzed in an ice bath with aq sat. NH4Cl (10 mL), the layers
were separated, and the aqueous phase was extracted with Et2O (2
× 10 mL). The combined organic layers were dried (Na2SO4) and
evaporated to dryness in vacuo. The crude product obtained was pu-
rified by flash chromatography (silica gel, hexane–EtOAc).
13C NMR (75 MHz, CDCl3): d = 55.9 (2 × OCH3), 78.7 (CHOH),
98.6 (CI), 110.7, 110.9, 119.6, 128.1, 128.5, 129.3, 134.9, 139.5,
145.6, 148.5, 148.9.
HRMS (EI): m/z [M]+ calcd for C15H15IO3: 370.0065 (100.0%),
371.0099 (16.2%); found: 370.0060 (100.0%), 371.0097 (16.9%).
(2-Chlorophenyl)(2-iodophenyl)methanol (4c)
Starting from 3c (80 mL, 0.71 mmol), 4c was synthesized according
to GP1. Column chromatography (hexane–EtOAc, 7:1) gave a col-
orless oil (230 mg, C13H10ClIO, M = 344.57 g/mol, 94%).
IR (neat): 3268, 3060, 2904, 1592, 1574, 1563, 1460, 1435, 1332,
1304, 1269, 1229, 1199, 1181, 1159, 1128, 1111, 1052, 1026, 1005,
942, 908, 867, 852, 815, 730, 688, 665, 637 cm–1.
Addition of ortho-Iodophenylcerium Species 5 to Ketones; Gen-
eral Procedure 2
1H NMR (300 MHz, CDCl3): d = 2.98 (br s, 1 H, OH), 6.29 (s, 1 H,
CHOH), 7.02 (m, 1 H, ArH), 7.25–7.35 (m, 6 H, ArH), 7.88 (d,
3J = 7.9 Hz, 1 H, ArH).
Anhyd CeCl3 (370 mg, 1.5 mmol) was suspended in anhyd THF (2
mL) in a Schlenk flask and stirred for 12 h at r.t. In a second Schlenk
flask, 1,2-diiodobenzene (1; 495 mg, 1.5 mmol) was dissolved in
anhyd THF (5 mL) under argon. After cooling to –30 °C, isopropyl-
magnesium chloride (2.0 M solution in THF, 0.75 mL) was added
dropwise and the resulting orange colored mixture was warmed to
–20 °C over a period of 20 min. The reaction was monitored by GC-
MS. Both flasks were cooled to –78 °C and the freshly prepared
Grignard reagent was added slowly to the CeCl3 suspension by
means of a syringe. The mixture was warmed to r.t. to ensure for-
mation of organocerium species by transmetalation. After cooling
again to –78 °C, a solution of ketone 6 (1 mmol) in THF (2 mL) was
added and the mixture was allowed to warm up to r.t. overnight. Af-
ter dilution with Et2O (10 mL), the mixture was hydrolyzed in an ice
bath with aq sat. NH4Cl (10 mL), the layers were separated, and the
aqueous phase was extracted with Et2O (2 × 10 mL). The combined
organic layers were dried (Na2SO4) and evaporated to dryness in
vacuo. The crude product obtained was purified by flash chroma-
tography (silica gel, hexane–EtOAc).
13C NMR (75 MHz, CDCl3): d = 76.4 (CHOH), 99.7 (CI), 127.0
(CCl), 128.4, 128.46, 128.51, 129.1, 129.6, 129.7, 133.8, 139.5,
139.7, 143.8.
HRMS (EI): m/z [M]+ calcd for C13H10ClIO: 343.9465 (100.0%),
345.9435 (32.0%), 344.9498 (14.1%), 346.9469 (4.5%); found:
343.9459 (100.0%), 345.9434 (34.0%),
346.9465 (5.4%).
344.9485 (16.3%),
(3-Bromophenyl)(2-iodophenyl)methanol (4d)
Starting from 3d (64 mL, 0.54 mmol), 4d was synthesized according
to GP1. Column chromatography (hexane–EtOAc, 7:1) gave a col-
orless oil (203 mg, C13H10BrIO, M = 389.03 g/mol, 97%).
IR (neat): 3323, 3059, 1592, 1567, 1462, 1431, 1180, 1115, 1071,
1030, 1008, 885, 778, 755, 725, 699, 668 cm–1.
1H NMR (300 MHz, CDCl3): d = 3.01 (s, 1 H, OH), 6.00 (s, 1 H,
CHOH), 7.01 (m, 1 H, ArH), 7.20 (t, 3J = 7.8 Hz, 1 H, ArH), 7.30–
3
7.43 (m, 4 H, ArH), 7.59 (s, 1 H, ArH), 7.85 (d, J = 7.8 Hz, 1 H,
ArH).
(2-Iodophenyl)phenylmethanol (4a)
Starting from 3a (100 mL, 0.98 mmol), 4a was synthesized accord-
ing to GP1. Column chromatography (hexane–EtOAc, 4:1) gave a
colorless oil (270 mg, C13H11IO, M = 310.13 g/mol, 89%).
13C NMR (75 MHz, CDCl3): d = 78.3 (CHOH), 98.7 (CI), 122.7
(CBr), 125.9, 128.4, 128.8, 129.8, 130.1, 130.2, 130.9, 139.7, 144.5,
144.8.
IR (neat): 3326, 3059, 3027, 2897, 1584, 1562, 1493, 1451, 1434,
1308, 1266, 1232, 1181, 1114, 1077, 1021, 1005, 948, 915, 850,
820, 744, 718, 695, 670, 640 cm–1.
HRMS (EI): m/z [M]+ calcd for C13H10BrIO: 387.8960 (100.0%),
389.8939 (97.3%), 388.8993 (14.1%), 390.8973 (13.7%); found:
Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York

2822
J. Cvengroš et al.
PRACTICAL SYNTHETIC PROCEDURES
387.8957 (100.0%), 389.8943 (99.1%), 388.8965 (19.5%),
390.8967 (15.2%).
1H NMR (300 MHz, CDCl3): d = 2.45 (s, 3 H, CH3), 3.71 (br s, 1 H,
3
OH), 5.99 (s, 1 H, CHOH), 6.89 (t, J = 7.8 Hz, 1 H, ArH), 7.24–
7.33 (m, 2 H, ArH), 7.41–7.49 (m, 2 H, ArH), 7.73 (d, 3J = 7.8 Hz,
1 H, ArH), 7.96 (s, 1 H, ArH).
(2-Iodophenyl)(1-tritylpyrrolidin-2-yl)methanol (4e)
Starting from 3e (342 mg, 1 mmol), 4e was synthesized according
to GP1. Column chromatography (hexane–EtOAc, 9:1) gave a
white solid (513 mg, C30H28INO, M = 545.45 g/mol, 94%); mp
103 °C.
13C NMR (75 MHz, CDCl3): d = 26.5 (CH3), 78.2 (CHOH), 98.5
(CI), 127.0, 127.4, 128.2, 128.50, 128.54, 129.4, 131.8 (ArC), 136.9
(CC=O), 139.4 (CHCI), 142.8 (ArC), 145.0 (CCI).
HRMS (EI): m/z [M]+ calcd for C15H13IO2: 351.9960 (100.0%),
352.9994 (16.2%); found: 351.9953 (100.0%), 352.9985 (16.6%).
IR (neat): = 2970, 1596, 1488, 1446, 1203, 1083, 1032, 1008, 937,
904, 850, 743, 661, 632, 610 cm–1.
1H NMR (300 MHz, CDCl3): d = 0.02 (m, 1 H, NCH2CH2), 0.70 (m,
1 H, NCH2CH2), 1.21–1.33 (m, 2 H, NCHCH2), 3.12 (m, 1 H,
NCH2), 3.24 (m, 1 H, NCH2), 4.20 (br s, 1 H, OH), 4.27 (m, 1 H,
NCH), 5.12 (d, 3J = 3.6 Hz, 1 H, CHOH), 6.91 (m, 1 H, ArH), 7.19–
7.34 (m, 10 H, ArH), 7.54–7.69 (m, 8 H, ArH).
1-(2-Iodophenyl)-1-phenylethanol (7a)13
Starting from 6a (100 mg, 0.83 mmol), 7a was synthesized accord-
ing to GP2. Column chromatography (hexane–EtOAc, 10:1) gave a
colorless oil (143 mg, C14H13IO, M = 324.16 g/mol, 53%).
IR (neat): 3518, 3056, 2978, 1672, 1581, 1493, 1446, 1427, 1371,
1325, 1271, 1224, 1126, 1069, 1028, 1007, 908, 756, 725, 699, 648
cm–1.
13C NMR (75 MHz, CDCl3): d = 24.6 (NCH2CH2), 26.8 (NCHCH2),
53.6 (NCH2), 61.4 (NCH), 76.5 (CPh3), 78.4 (CHOH), 95.7 (CI),
126.4, 127.5, 127.65, 127.74, 128.2, 128.6, 129.9, 139.0, 144.2
(ArC).
1H NMR (300 MHz, CDCl3): d = 2.03 (s, 3 H, CH3), 3.34 (br s, 1 H,
OH), 7.02 (dt, J = 1.6, 7.7 Hz, 1 H, ArH), 7.29–7.34 (m, 5 H, ArH),
7.48 (dt, J = 1.2, 7.5 Hz, 1 H, ArH), 7.88 (dd, J = 1.5, 7.9 Hz, 1 H,
ArH), 7.94 (dd, J = 1.1, 7.8 Hz, 1 H, ArH).
(E)-1-(2-Iodophenyl)but-2-en-1-ol (4f)
Starting from 3f (59 mL, 0.71 mmol), 4f was synthesized according
to GP1. Column chromatography (hexane–EtOAc, 7:1) gave a pale
yellow oil (153 mg, C10H11IO, M = 274.10 g/mol, 78%).
13C NMR (75 MHz, CDCl3): d = 30.7 (CH3), 78.1 (COH), 96.5 (CI),
126.5, 127.1, 128.0, 128.2, 128.3, 129.2, 142.6, 147.1, 147.5 (ArC).
IR (neat): 3316, 3056, 2912, 2359, 2339, 1668, 1583, 1561, 1461,
1434, 1376, 1308, 1193, 1104, 1074, 1003, 962, 926, 838, 752, 720,
663 cm–1.
1-(1-Benzylpyrrolidin-2-yl)-1-(2-iodophenyl)ethanol (7b)
Starting from 6b (615 mg, 3.02 mmol), 7b was synthesized accord-
ing to GP2. Column chromatography (hexane–EtOAc, 9:1) gave a
yellow oil (1.07 g, C19H22INO, M = 407.29 g/mol, 87%).
1H NMR (300 MHz, CDCl3): d = 1.73 (ddd, J = 0.9, 1.4, 6.5 Hz, 3
H, CH3), 2.55 (br s, 1 H, OH), 5.37 (d, J = 5.9 Hz, 1 H, CHOH), 5.61
(qdd, J = 1.5, 6.4, 15.3 Hz, 1 H, CH3CH), 5.85 (m, 1 H,
CH3CHCH), 6.98 (td, J = 1.7, 7.7 Hz, 1 H, ArH), 7.38 (td,
J = 0.9, 7.7 Hz, 1 H, ArH), 7.52 (dd, J = 1.7, 7.8 Hz, 1 H, ArH), 7.83
(dd, J = 1.1, 7.9 Hz, 1 H, ArH).
IR (neat): 2969, 2802, 1556, 1494, 1452, 1372, 1298, 1205, 1074,
1002, 757, 700 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.78 (m, 2 H, NCH2CH2), 1.87 (s,
3 H, CH3), 2.14 (m, 2 H, NCHCH2), 2.48 (m, 1 H, NCH2), 2.94 (m,
1 H, NCH2), 3.17 (s, 2 H, PhCH2), 4.31 (t, 3J = 7.5 Hz, 1 H, NCH),
5.10 (br s, 1 H, OH), 6.89 (dd, 3J = 7.5 Hz, 4J = 1.5 Hz, 1 H, ArH),
7.11 (d, 3J = 6.6 Hz, 2 H, C6H5), 7.22–7.32 (m, 3 H, C6H5), 7.41 (dd,
3J = 7.8 Hz, 4J = 1.5 Hz, 1 H, ArH), 8.00 (dd, 3J = 7.8 Hz, 4J = 1.5
Hz, 1 H, ArH), 8.18 (dd, 3J = 7.8 Hz, 4J = 1.5 Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 17.9 (CH3), 77.8 (CHOH), 98.2
(CI), 127.6, 128.4, 128.6, 129.2, 131.8, 139.4, 145.1.
HRMS (EI): m/z [M]+ calcd for C10H11IO: 273.9855 (100.0%),
274.9888 (10.8%); found: 273.9842 (100.0%), 274.9875 (13.4%).
13C NMR (75 MHz, CDCl3): d = 24.2 (NCH2CH2), 24.7 (CH3), 27.2
(NCHCH2), 54.6 (PhCH2), 59.9 (NCH2), 67.4 (CCH3), 73.4 (NCH),
93.9 (CI), 126.6, 127.89, 127.92, 128.0, 128.26, 128.33, 139.4,
142.3, 150.1 (ArC).
(Z)-2-Bromo-1-(2-iodophenyl)-3-phenylprop-2-en-1-ol (4g)
Starting from 3g (100 mg, 0.47 mmol), 4g was synthesized accord-
ing to GP1. Column chromatography (hexane–EtOAc, 7:1) gave a
pale brown oil (116 mg, C15H12BrIO, M = 415.06 g/mol, 59%).
HRMS (EI): m/z [M – CH3]+ calcd for C19H22INO: 392.0511
(100.0%), 393.0545 (19.5%); found: 392.0508 (100.0%), 393.0540
(24.6%).
IR (neat): 3346, 3054, 3024, 2919, 1688, 1637, 1598, 1584, 1564,
1490, 1462, 1445, 1434, 1260, 1189, 1116, 1064, 1029, 948, 907,
861, 809, 750, 726, 657, 620 cm–1.
1H NMR (300 MHz, CDCl3): d = 2.79 (br s, 1 H, OH), 5.72 (s, 1 H,
CHOH), 7.08 (dt, J = 1.5, 7.5 Hz, 1 H, ArH), 7.34–7.47 (m, 5 H,
ArH), 7.64–7.69 (m, 3 H, ArH), 7.90 (dd, J = 1.2, 7.8 Hz, 1 H,
ArH).
1-(2-Iodophenyl)cyclohexanol (7c)
Starting from 6c (0.2 mL, 1.92 mmol), 7c was synthesized accord-
ing to GP2. Column chromatography (hexane–EtOAc, 50:1) gave a
white powder (384 mg, C12H15IO, M = 302.15 g/mol, 66%).
13C NMR (75 MHz, CDCl3): d = 82.2 (CHOH), 99.4 (CI), 126.7,
128.2, 128.3, 128.5, 128.6, 129.1, 130.1, 130.4, 135.1, 139.7, 142.1.
IR (neat): 3348, 3054, 2927, 2857, 1557, 1451, 1428, 1396, 1354,
1320, 1281, 1264, 1190, 1150, 1138, 1063, 1032, 1013, 1000, 968,
946, 906, 899, 861, 844, 716, 657, 624 cm–1.
HRMS (EI): m/z [M]+ calcd for C15H12BrIO: 413.9116 (100.0%),
415.9096 (97.3%), 414.9150 (16.2%), 416.9129 (15.8%), 415.9183
(1.2%), 417.9163 (1.2%); found: 413.9112 (100.0%), 415.9093
(96.7%), 414.9146 (18.1%), 416.9131 (16.4%).
1H NMR (300 MHz, CDCl3): d = 1.28–1.42 (m, 1 H, CH), 1.69–
1.91 (m, 5 H, CH), 2.02–2.21 (m, 4 H, CH), 2.32 (s, 1 H, OH), 6.92
(t, J = 7.4 Hz, 1 H, ArH), 7.35 (t, J = 7.8 Hz, 1 H, ArH), 7.62 (t,
J = 7.9 Hz, 1 H, ArH), 7.99 (t, J = 7.9 Hz, 1 H, ArH).
1-{3-[Hydroxy-(2-iodophenyl)methyl]phenyl}ethanone (4h)
Starting from 3h (186 mg, 1.25 mmol), 4h was synthesized accord-
ing to GP1. Column chromatography (hexane–EtOAc, 8:2) gave a
colorless foam (312 mg, C15H13IO2, M = 352.17 g/mol, 71%).
13C NMR (75 MHz, CDCl3): d = 22.0, 25.3, 36.0, 74.0 (COH), 93.5
(CI), 127.0, 128.2, 128.6, 143.0, 148.4 (ArC).
HRMS (EI): m/z [M]+ calcd for C12H15IO: 302.0168 (100.0%),
303.0201 (13.0%); found: 302.0162 (100.0%), 303.0198 (15.3%).
IR (neat): 3396, 3060, 2973, 2870, 1671, 1599, 1583, 1562, 1460,
1433, 1357, 1269, 1167, 1114, 1035, 977, 955, 916, 826, 792, 761,
735, 692, 670, 645 cm–1.
Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York

PRACTICAL SYNTHETIC PROCEDURES
A Concise Synthesis of ortho-Iodobenzyl Alcohols
2823
2-(2-Iodophenyl)-4-phenylbutan-2-ol (7d)
1-(2-Iodophenyl)ethanone (7h)
Starting from 6d (0.1 mL, 0.67 mmol), 7d was synthesized accord-
ing to GP2. Column chromatography (hexane–EtOAc, 10:1) gave a
yellowish oil (170 mg, C16H17IO, M = 352.21 g/mol, 72%).
Starting from 6h (51 mg, 0.50 mmol), 7h was synthesized according
to GP2. Column chromatography (hexane–EtOAc, 9:1) gave a yel-
low liquid (101 mg, C8H7IO, M = 246.05 g/mol, 82%).
IR (neat): 3460, 3024, 2927, 1602, 1557, 1496, 1454, 1427, 1372,
1263, 1122, 1063, 1004, 882, 757, 725, 699 cm–1.
IR (neat): 2919, 2359, 1580, 1560, 1460, 1422, 1354, 1280, 1241,
1165, 1088, 1035, 1014, 958, 756, 719, 642, 631 cm–1.
1H NMR (300 MHz, CDCl3): d = 1.83 (s, 3 H, CH3), 2.24 (m, 1 H,
CH), 2.36 (br s, 1 H, OH), 2.48 (m, 1 H, CH), 2.60 (m, 1 H, CH),
2.84 (m, 1 H, CH), 6.96 (t, 3J = 7.5 Hz, 1 H, ArH), 7.22–7.35 (m, 5
H, ArH), 7.41 (t, J = 7.4 Hz, 1 H, ArH), 7.79 (d, 3J = 7.8 Hz, 1 H,
ArH), 8.04 (d, 3J = 7.8 Hz, 1 H, ArH).
1H NMR (300 MHz, CDCl3): d = 2.59 (s, 3 H, CH3), 7.09 (dd,
3J = 7.5 Hz, 1 H, ArH), 7.36–7.46 (m, 2 H, ArH), 7.91 (d, 3J = 7.5
Hz, 1 H, ArH).
13C NMR (75 MHz, CDCl3): d = 29.5 (CH3), 90.9 (CI), 128.0,
128.3, 131.8, 140.9, 144.1 (ArC), 201.8 (C=O).
13C NMR (75 MHz, CDCl3): d = 28.5 (CH3), 30.8 (CH2Ph), 42.7
(CH2), 75.8 (COH), 93.1 (CI), 125.8, 127.8, 128.2, 128.4, 128.5,
128.7, 142.2, 142.8, 147.6 (ArC).
HRMS (EI): m/z [M]+ calcd for C8H7IO: 245.9542 (100.0%),
246.9575 (8.7%); found: 245.9539 (100.0%), 246.9601 (9.2%).
HRMS (EI): m/z [M]+ calcd for C16H17IO: 352.0324 (100.0%);
found: 352.0316 (100.0%).
1-Chloro-1,3-dihydro-3,3-bis(trifluoromethyl)-1,2-benziodox-
ole (10)5b
To a solution of 7g (5.92 g, 15.99 mmol) in CCl4 (6 mL) was added
freshly prepared tert-butyl hypochlorite14 (1.8 mL, 16.54 mmol) at
0 °C. The reaction mixture was maintained at 0 °C for 30 min. After
warming to r.t., and filtration the title compound 10 was obtained as
yellow crystals (6.06 g, C9H4ClF6IO, M = 404.48 g/mol, 94%).
2-(2-Iodophenyl)-6-methylhept-5-en-2-ol (7e)
Starting from 6e (63 mg, 0.50 mmol), 7e was synthesized according
to GP2. Column chromatography (hexane–EtOAc, 9:1) gave a col-
orless oil (88 mg, C14H19IO, M = 330.20 g/mol, 53%).
IR (neat): 3448, 2967, 2923, 1558, 1454, 1428, 1264, 1122, 1074,
1046, 1003, 884, 828, 757, 722 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.72 (m, 2 H, ArH), 7.82 (m, 1 H,
ArH), 8.07 (d, 3J = 8.4 Hz, 1 H, ArH).
1H NMR (300 MHz, CDCl3): d = 1.47 (s, 3 H, CH3), 1.64 (s, 3 H,
CH3), 1.69 (s, 3 H, CH3), 1.87–1.92 (m, 4 H, CH2), 5.09 (br s, 1 H,
13C NMR (75 MHz, CDCl3): d = 85.2 (CCF3), 113.4 (CI), 122.9 (q,
1JC,F = 289.5 Hz, CF3), 128.5, 129.7, 131.6, 132.1, 133.8 (ArC).
3
OH), 6.86 (dd, 3J = 7.2 Hz, 1 H, ArH), 7.31 (dd, J = 7.2 Hz, 1 H,
19F NMR (282 MHz, CDCl3): d = –75.7 (s, CF3).
3
ArH), 7.67 (d, J = 7.2 Hz, 1 H, ArH), 7.94 (d, J = 7.2 Hz, 1 H,
3
HRMS (EI): m/z [M – CF3]+ calcd for C9H4ClF6IO: 334.8947;
found: 334.8938.
ArH).
13C NMR (75 MHz, CDCl3): d = 17.7 (CH3), 23.0 (CH3), 25.7
(CH3), 28.2 (CH2), 40.4 (CH2), 76.0 (COH), 93.0 (CI), 123.9
(CH=C), 127.7, 127.9, 128.4 (ArC), 132.4 (C=CH), 142.6, 147.9
(ArC).
Acknowledgment
Financial support from ETH Zurich is gratefully acknowledged.
D.S. was supported by a fellowship within the Postdoc-Program of
the German Academic Exchange Service (DAAD).
HRMS (EI): m/z [M + Ag]+ calcd for C14H19IO: 436.9532 (100.0%),
437.9565 (15.1%); found: 436.9528 (100.0%), 437.9562 (14.5%).
1,1,1,3,3,3-Hexafluoro-2-(2-iodophenyl)propan-2-ol (7g)
A modified GP1 was applied: In a Schlenk flask, 1,2-diiodobenzene
(2.6 g, 7.9 mmol) was dissolved in anhyd THF (26 mL) under argon.
After cooling to –30 °C, isopropylmagnesium chloride (2.0 M solu-
tion in THF, 4 mL) was added dropwise and the resulting orange
colored mixture was warmed to –20 °C over a period of 20 min and
subsequently cooled down to –78 °C. A solution of hexafluoroace-
tone (2 mL, 15.9 mmol, 2 equiv) in THF (10 mL) was added via
cannula and the mixture was allowed to warm up to r.t. overnight.
After dilution with Et2O (30 mL), the mixture was hydrolyzed in an
ice bath with aq sat. NH4Cl (30 mL), the layers were separated, and
the aqueous phase was extracted with Et2O (3 × 30 mL). The com-
bined organic layers were dried (Na2SO4) and evaporated to dryness
in vacuo. The pure product was obtained after purification by flash
chromatography (silica gel, pentane–Et2O, 50:1, then 3:1) as a col-
orless oil (2.3 g, C9H5F6IO, M = 370.03 g/mol, 80%).
References
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IR (neat): 3456, 3382, 1587, 1566, 1472, 1437, 1423, 1171, 1102,
1054, 1012, 963, 947, 921, 868, 757, 727, 698, 678, 638, 630 cm–1.
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1H NMR (300 MHz, CDCl3): d = 4.55 (br s, 1 H, OH), 7.12 (dt,
J = 1.5, 8.1 Hz, 1 H, ArH), 7.44 (dt, J = 1.2, 8.4 Hz, 1 H, ArH), 7.65
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W. H.; Dess, D.; Ross, M. R.; Martin, J. C. J. Org. Chem.
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13C NMR (75 MHz, CDCl3): d = 78.8 (q, J = 29.9 Hz, COH), 90.5
(CI), 122.6 (q, J = 290.1 Hz, CF3), 128.0, 129.7, 130.0, 131.4, 144.7
(ArC).
19F NMR (188 MHz, CDCl3): d = –73.4.
HRMS (EI): m/z [M]+ calcd for C9H5F6IO: 369.9289 (100.0%),
370.9323 (9.7%); found: 369.9286 (100.0%), 370.9335 (9.6%).
Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York

2824
J. Cvengroš et al.
PRACTICAL SYNTHETIC PROCEDURES
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Synthesis 2009, No. 16, 2818–2824 © Thieme Stuttgart · New York