P-Iodinations in hydrocarbon media: Continuous flow reactor application

Article abstract of DOI:10.1016/j.tetlet.2011.10.110

Regiospecific iodination of aryl amines, that is, aryl compounds possessing strong electron donating groups (EDG's) in the p-position, is described. This procedure features not only the unique use of hydrocarbon media for such substitutions but also the absence of any oxidants aside from iodine itself. Further potential of this hydrocarbon media based electrophilic aromatic substitution is demonstrated by the coupling of the iodination with an in situ halogen/lithium exchange and product forming nucleophilic addition in a batch process. The protocol was ultimately scaled to a continuous flow reactor using an isolated p-iodoarylamine. Constituted as described, these procedures possess enhanced atom-economical, green and safety aspects compared to existing literature protocols.

Full text of DOI:10.1016/j.tetlet.2011.10.110

Tetrahedron Letters 52 (2011) 7141–7145
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
p-Iodinations in hydrocarbon media: continuous flow reactor application
D. W. Slocum a,b, , Kristen C. Tekin a, Quang Nguyen a, Paul E. Whitley a,b, Thomas K. Reinscheld a,b
,
⇑
Begum Fouzia a
a Department of Chemistry, Western Kentucky University, Bowling Green, KY 42101, USA
b KinetiChem Inc., 19100 Von Karman Ave. Suite 400, Irvine, CA 92612, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Regiospecific iodination of aryl amines, that is, aryl compounds possessing strong electron donating
groups (EDG’s) in the p-position, is described. This procedure features not only unique use of hydrocarbon
media for such substitutions but also the absence of any oxidants aside from iodine itself. Further poten-
tial of this hydrocarbon media based electrophilic aromatic substitution is demonstrated by the coupling
of the iodination with an in situ halogen/lithium exchange and product forming nucleophilic addition in a
batch process. The protocol was ultimately scaled to a continuous flow reactor using an isolated p-iodo-
arylamine. Constituted as described, these procedures possess enhanced atom-economical, green and
safety aspects compared to existing literature protocols.
Received 23 September 2011
Accepted 19 October 2011
Available online 25 October 2011
Keywords:
Iodination
Continuous flow reactor
Electrophilic aromatic substitution
Green chemistry
Ó 2011 Elsevier Ltd. All rights reserved.
Halogen/metal exchange
Electrophilic aromatic substitution (EAS) has long been the
mainstay for the preparation of specifically substituted aromatic
compounds. In spite of the many protocols developed for such sub-
stitutions, several drawbacks persist, for example, lack of regiose-
lectivity, strong acid conditions, oxidative conditions and metal
and/or acid containing hazardous waste streams. Not all draw-
backs will exist simultaneously, but seldom will fewer than two
of them be absent. In spite of these drawbacks, chemists have been
able to devise conditions and modify reagents and aromatic sub-
strates to effect reasonably efficient syntheses of numerous substi-
tuted arenes and hetarenes.
Halogenated arenes, particularly arylbromides and -iodides, are
useful intermediates for further synthetic elaboration. Procedures
for such elaborations are the halogen/metal (X/Li) exchange, Grig-
nard formation and Pd intermediate formation. The X/Li exchange
and Grignard intermediates provide entry to countless nucleophilic
additions and substitutions while Pd intermediate formation leads
Over the past two decades or so a number of papers have ap-
peared describing novel routes to regiospecific p-iodination and
p-bromination of arenes. Usually, but not exclusively, the aro-
matic substrates are activated, often highly activated, towards
EAS. In each case an oxidant was found necessary. A few exam-
ples of these oxidants are: KIO3 or NaIO4,12 NaNO3 or NaNO2,6
1
3
[S2O2ꢀ],2,8,9,16 UreaꢁH2O2 solvent free complex,13 HgO,10 CrO3
5
8
and Selectfluor™.15 Solvent systems utilized were combinations
of acetonitrile/CHCl3,14–16 CH2Cl2 Ac2O/HOAc/H2SO4
or
10
3–5,9,11,12
aqueous ether/alcohol.1,2,7 Four distinct sources of iodine have
been utilized, KI,1,2,11 ICl,7 I2
and N-iodosuccina-
3,5,6,8–10,12,13,15,16
mide (NIS).4,14 One procedure involving KI invoked an intermedi-
ate produced by thallation.11 Although these approaches provide
regioselectivity, they do so for the most part at the expense of
raising both the hazardous components of the reactions and the
toxic waste streams from the reactions. In these days of atom-
economy, sustainability and overall emphasis on green chemistry,
these procedures do not appear especially attractive.
to Heck, Stille, Suzuki and
reactions.
a multitude of related coupling
We now bring to the community’s attention the regiospecific
p-iodination of eleven activated aryl amines under novel condi-
tions that are both safer and greener than those in the literature
(Table 1). These conditions feature use of I2 in cyclohexane media
(Eq. 1). The reactions are mostly run at room temperature in the
presence of an aqueous phase of saturated Na2CO3 to neutralize
the HI generated. Yields were lower when the HI was not neutral-
ized. It is important that we point out, in addition to the novel use
of cyclohexane as the reaction medium, that no external oxidant is
necessary. Compared to the extant conditions for these iodinations,
the absence of oxidative catalyst and the use of hydrocarbon media
Classically, arylbromides and -chlorides are prepared using Cl2
or Br2 in an EAS reaction catalyzed by a small amount of an oxida-
tive catalyst in a halogenated solvent. Textbook preparations of
aryliodides often invoke use of I2 and HNO3. This latter protocol af-
fords only modest yields. Neither of these approaches provides reg-
iospecific aromatic substitution. Classically, all four halides can be
regiospecificly prepared via diazonium salts.
⇑
Corresponding author. Tel.: +1 270 745 5239; fax: +1 270 745 5361.
E-mail address: donald.slocum@wku.edu (D. W. Slocum).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.110

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D. W. Slocum et al. / Tetrahedron Letters 52 (2011) 7141–7145
Table 1
GC and isolated yields of p-iodinated aryl amines
Substrates
Reaction time (h)
GC yield (%)
Isol. yield (%)
Lit. mp (°C)
Exp. mp (°C)
Aniline (1)
7
3
0.5
2
4.5
91
95
95
90
95
21
95
85
81
95
70c
60
73
70
80
75
12
80
64
65
80
45
63.5–64.017
8618
63.5–64.5
86.5–87.0
40.5–42.0
Oil
81.5–82
Oil
61.5–63.0
56.0–56.5
48.0–49.0
Oil
2-Toluidine (2)
3-Toluidine (3)
N-Methylaniline (4)
DMAa (5)
2-Methyl-DMA (6)
3-Methyl-DMA (7)
3,5-Dimethyl-DMA (8)
3-Methoxy-DMA (9)
DEAb (10)
49.5–5019
30–3220
80–8112
24
Unknown
Unknown
54.5–55.021
Unknown
26–2722
24
24
24
6
Acetanilide (11)
24
188–1895
182.0–183.0
a
b
c
N,N-Dimethylaniline.
N,N-Diethylaniline.
NIS utilized as the iodinating agent (60 °C).
afford a much safer, greener and unique approach to these unusual
p-substitutions.
N
R'
R'
H
R2N
R2N
r.t.
HI (neutralized)
+
I2
+
I
cyclohexane/
aq. Na2CO3
I
Figure 1.
ð1Þ
Initial studies of the solvent media involved examination of 80%
aqueous ethanol, ethanol, toluene, pentane, and hexanes in addi-
tion to cyclohexane. Most of these media afforded yields of
iodination that were 10–20% lower than those realized using cyclo-
hexane although for a few substrates yields obtained in hexanes
and pentane were nearly comparable. Most of these initial runs
were performed at a 0.67 M concentration. Once cyclohexane
was chosen, further experiments were performed at 1.0 M,
1.67 M, and 2.2 M with 1.67 M ultimately chosen as the routine
concentration. For maximum conversion, the reaction times varied
for many of the anilines from 0.5 to 7 h, but for all the substituted
DMA’s and acetanilide 24 h was necessary. All the iodinations save
that for acetanilide (11) utilized I2. For acetanilide very low yields
were obtained using this reactant; yields were greatly increased by
switching to NIS as the sources of iodine. The other substrate
affording a low yield, 2-methyl-DMA (6), also experienced signifi-
cant yield enhancement (64%) using NIS. We attribute greater
iodination reactivity to NIS compared to I2 itself for these iodina-
tions as a result of the enhanced yields observed for these two sub-
strates. Isolated yields were not optimized. Curiously, we found no
cases where mild heating provided benefit for iodinations using I2.
In two instances heating caused some decomposition.
steric bulk to inhibit the transition state for ortho-iodination. This
would be minimally true for both aniline (–NH2 substituent) and
phenol (–OH substituent) (not studied here).
The observation that an improved p-/o-ratio for aniline iodin-
ated in cyclohexane compared to other media suggests, in addition
to higher yields, that even greater regioselectivities can be realized
under these conditions. It should be noted that both o- and m-tolu-
idine are each p-iodinated with no detection of any o-iodinated
product (Table 1).
Mechanistically, some evidence has been accumulated that sup-
ports an electrophilic substitution even under these non-polar con-
ditions. The p-regiospecificity alone suggests an ortho-inhibited
electrophilic mechanism. Moreover, protection from light radiation
during several repeat runs for the iodination of DMA brought no
observed change in reaction profile. Lastly, the low GC yield
(21%) observed for the p-iodination of the 2-methylDMA, 6, with
I2 suggests an increase in the transition state energy by an inhibi-
tion of resonance stabilization by steric inference ( Fig. 1). The
canonical structure involving delocalization of the positive charge
to nitrogen is the principal contributor to the transition state reso-
nance structure for p-iodination. Its inhibition as depicted in Figure
1 raises the transition state energy resulting in a significantly re-
tarded reaction.
Use of I2 in the reaction generates HI which must be neutral-
ized to move the reaction towards completion. Accordingly, all of
these reactions save one have been run as two-phase systems
with the second phase being constituted of saturated Na2CO3.
This procedure did not work well for acetanilide, a less activated
substrate. NIS was found to afford an acceptable yield in this in-
stance. Use of NIS avoided the need for the use of aqueous
Na2CO3.
A comparison was made of the yields afforded by our procedure
and several of those found in the literature (Table 2). We note that
for aniline itself, not only is a relatively high yield obtained, there is
an improved para/ortho ratio. For the most part we conclude that a
substituent with any dimension whatsoever will possess sufficient
Table 2
Reported yields from p-iodinationsa
Substrate
Overall % yield
% o-
% p-
The success of this approach to the synthesis of p-iodinated are-
nes provides a potential for, essentially, a one-pot elaboration of
the iodoarene. Both the X/Li exchange and Grignard formation
could be effected by the simple expedient of drawing off the aque-
ous layer and directly subjecting the cyclohexane medium contain-
ing the generated iodoarene to either an alkyllithium reagent or a
Grignard-forming reagent. This strategy cannot be employed for
those arenes containing acidic hydrogens. Such a strategy is out-
lined for DMA (Eq. 2).
PhNH2
PhNHAc
DMA
(65)1, (63)2, 373, 20–8313
801, (47)3, (80)8
831, 582
(96) 60
(70) 45
(6.5)1(8)2
Not reported
Not reported
(4.5)c
0
(<1)
(58.5)1, (55)2
b
PhNH2
(91.4)
PhNHAcb
DMAb
(95) 75
a
b
c
Numbers in parenthesis represent GC yields.
This Letter.
0.5% Diiodo product.

D. W. Slocum et al. / Tetrahedron Letters 52 (2011) 7141–7145
7143
OH
N
Ph2CO
I2
n-BuLi
Ph
p-IDMA
aq. Na2CO3
p-LiDMA
r.t.
cyclohexane/
ð2Þ
Ph
5 min.
aq. Na2CO3
N
phase
12
DMA
The exchange was carried out using our X/Li exchange protocol
which features use of only a slight excess of n-BuLi at ambient tem-
perature.23 The synthesized p-substituted triarylcarbinol was char-
acterized by melting point comparison to a literature value,24 GC/
MS and by NMR. As compared to our experience with bromine/
lithium exchanges, the iodo/lithium exchange provides a signifi-
cantly larger amount of butylated aryl impurity (up to 22%). The
butyl byproduct is presumably more prevalent due to the resulting
iodobutane, formed after iodo/lithium exchange, being a more
reactive electrophile than bromobutane, formed after bromo/lith-
ium exchange. Therefore, this reaction must be quenched quickly
with the benzophenone, before the exchanged aryllithium has an
opportunity to react with the iodobutane. This phenomenon is
scale-dependent as well as temperature dependent.
In order to illustrate dependable scalability to our protocol, we
employed the use of a continuous reactor.25 Following a procedure
similar to that for the small batch study described previously, a
1 M 10/1 cyclohexane/THF (small amount of THF for solubility)
solution containing p-IDMA was fed into the continuous reactor
at a rate of 150 mL/min along with 1 M n-BuLi/ cyclohexane at a
like rate. Test run(s) where the exchange was quantified by trap-
ping with chlorotrimethylsilane (ClTMS) revealed that the ex-
change to produce p-LiC6H4NMe2 could be realized to an extent
of 97–98%, while providing only minute (<1%) quantities of the un-
wanted butylated aryl.
NMR’swereperformedonaJEOLEclipseECA500instrument. Melting
points were measured using Mel-TempÒ apparatus. Column chroma-
tography was performed using silica gel 60 Å, 65 ꢃ 250 mesh.
General iodination procedure
To a clean 50 mL round bottom flask equipped with a large stir
bar was added the substrate (10 mmol) followed by cyclohexane
(ca. 6.0 mL to maintain the reaction concentration of 1.67 M) and
an aqueous saturated solution of sodium carbonate (2.8 mL). Final-
ly, iodine beads (11 mmol) were added as a solid and the flask was
sealed with a septum and vented with a needle to the open atmo-
sphere. The reaction was allowed to stir for the specified time at
room temperature unless otherwise noted (see Table 1). The reac-
tion mixture was poured into a separatory funnel with the aid of
ethyl acetate or MTBE (2–3 mL) with additional aqueous saturated
sodium carbonate (1 mL). The organic layer was washed twice with
an aqueous saturated solution of sodium bisulfite (4 mL) and brine
(5 mL), dried over sodium sulfate and concentrated in vacuo to
provide crude iodinated product. The products were purified by
crystallization (if crystalline) from hexanes. Column chromatogra-
phy (ethyl acetate/hexanes) was performed on the oils.
4-Iodo-phenylamine (1)17
1H NMR (CDCl3) d 3.67 (broad s, NH2), 6.46–6.47 (d, J = 9.1 Hz,
2H), 7.39–7.41 (d, J = 9.2 Hz, 2H). 13C NMR d 79.5, 117.4, 138.0, 146.1.
Using two reactors in sequence, X/Li exchange (reactor 1) and
condensation with benzophenone (reactor 2) was effected to afford
the triphenylcarbinol, 12, in 63% isolated yield, which with an ex-
tended time period would correspond to a preparation of 1.7 kg/h.
This experiment portends that coupling of p-iodination in cyclo-
hexane followed by a X/Li exchange/derivatization sequence can
efficiently provide numerous value-added specifically substituted
aryl products in a rapid and scalable manner.
4-Iodo-2-methyl-phenylamine (2)18
1H NMR (CDCl3) d 2.11 (s, 3H), 3.44 (broad s, NH2), 6.43–6.45 (d,
J = 8.6 Hz, 1H), 7.28–7.30 (dd, J = 8.6, 2.3 Hz, 1H), 7.33 (s, 1H). 13C
NMR (CDCl3) d 17.2, 79.6, 116.9, 125.0, 135.6, 138.7, 144.4.
4-Iodo-3-methyl-phenylamine (3)19
1H NMR (CDCl3) d 2.32 (s, 3H), 3.01 (broad s, NH2), 6.26–6.28
(dd, J = 8.6, 2.9 Hz, 1H), 6.61–6.62 (d, J = 2.9 Hz, 1H), 7.47–7.51 (d,
J = 8.6 Hz, 1H). 13C NMR (CDCl3) d 28.1, 86.7, 114.9, 116.9, 139.3,
142.0, 146.6.
In summary, this study describes several novel accomplish-
ments and observations.
Chief among these are:
ꢂ A regiospecific electrophilic aromatic substitution that takes
place in nonpolar cyclohexane media and requires no external
oxidizing agent.
ꢂ A preliminary observation that for anilines, the para/ortho ratio
is improved under cyclohexane media conditions compared to
media conditions recorded in the literature.
(4-Iodo-phenyl)-methyl-amine (4)20
1H NMR (CDCl3) d 2.81 (s, 3H), 3.70 (broad s, NH), 6.38–6.39 (d,
J = 8.5 Hz, 2H), 7.42–7.43 (d, J = 9.2 Hz, 2H). 13C NMR (CDCl3) d 30.7,
77.8, 114.7, 137.8, 148.9.
(4-Iodo-phenyl)-dimethyl-amine (5)12
ꢂ An in situ coupling of the iodination and the X/Li exchange/
derivatization has been demonstrated. Also demonstrated is a
scalable X/Li exchange/derivatization using continuous flow
technology, thereby illustrating the potential of the process to
afford value added products on demand at gram to kg scale.
1H NMR (CDCl3) d 2.95 (s, 6H), 6.48–6.49 (dd, J = 9.2, 2.3 Hz, 2H),
7.45–7.47 (dd, J = 8.6, 1.8 Hz, 2H). 13C NMR (D6CO)26 d 39.5, 76.4,
114.8, 137.4, 150.4.
(4-Iodo-2-methyl-phenyl)-dimethyl-amine (6)
1H NMR (CDCl3) d 2.28 (s, 3H), 2.68 (s, 6H), 6.76–6.78 (d,
J = 8.6 Hz, 1H), 7.43-7.45 (dd, J = 8.6, 1.7 Hz, 1H), 7.48 (s, 1H). 13C
NMR (CDCl3) d 18.3, 44.1, 86.0, 120.6, 134.8, 135.4, 139.7, 152.7.
Experimental
General
(4-Iodo-3-methyl-phenyl)-dimethyl-amine (7)
All research chemicals were supplied by Aldrich Chemical Co. and
used as received unless otherwise noted. GC analysis was performed
on a Agilent 6850 instrument equipped with a FID detector and GC–
MS analysis was performed on an Agilent 5973 MSD instrument con-
taining a 6890 N Network system equipped with an FID detector.
Melting point = 61.0–62.0 °C; 1H NMR (CDCl3) d 2.37 (s, 3H),
2.91 (s, 6H), 6.30-6.33 (dd, J = 8.6, 2.9 Hz, 1H), 6.63–6.64 (d,
J = 2.8 Hz, 1H), 7.55–7.57 (d, J = 9.1 Hz, 1H). 13C NMR (CDCl3) d
28.5, 40.7, 85.0, 112.5, 114.4, 139.0, 141.5, 150.7.

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D. W. Slocum et al. / Tetrahedron Letters 52 (2011) 7141–7145
(4-Iodo-3,5-dimethyl-phenyl)-dimethyl-amine (8)21
1H NMR (CDCl3) d 2.44 (s, 6H), 2.91 (s, 6H), 6.49 (s, 2H). 13C NMR
(CDCl3) d 30.1, 40.7, 92.4, 111.9, 142.1, 150.2.
6H), 6.64–6.66 (d, J = 9.2 Hz, 2H), 7.07–7.09 (d J = 9.2 Hz, 2H),
7.22–7.30 (complex m, 10H); 13C NMR (CDCl3) d 40.6, 81.9,
111.8, 127.1, 127.9, 128.0, 129.0, 147.5, 149.7.
(4-Iodo-3-methoxy-phenyl)-dimethyl-amine (9)
(4-Dimethylamino-phenyl)-diphenyl-methanol (12) synthesis:
continuous halogen/lithium exchange/derivatization with
Synthetron™ S3T1 reactor
mp = 56.0-58.0 °C; 1H NMR (CDCl3) d 2.95 (s, 6H), 3.86 (s, 3H),
6.12–6.14 (dd, J = 8.6, 2.9 Hz, 1H), 6.19–6.20 (d, J = 2.8 Hz, 1H),
7.49–7.51 (d, J = 9.2 Hz, 1H). 13C NMR (CDCl3) d 40.7, 56.2, 69.3,
96.5, 107.4, 139.0, 152.3, 158.7.
A 25 mL solution of
5 (1.0 M) in anhydrous cyclohexane
including THF (2 mL, to ensure solubility) was prepared and trea-
ted with 25 mL of 1.0 M n-BuLi in cyclohexane (commercial 2.0 M
solution of n-BuLi in cyclohexane was diluted with cyclohexane
to achieve a final concentration of 1.0 M). Reagent solutions were
delivered through Teflon tubing using independent SYR-2200
dual programmable syringe pumps obtained from J-KEM Scien-
tific. Initial trials were conducted where each reagent solution
was fed into the reactor at 6 °C (chilled with a circulating chiller)
and exit stream was directed into a stirring 2.0 M solution of
ClTMS in cyclohexane (30 mL) held at 0 °C in an ice bath. Reagent
stream feed rates were 150 mL/min each, providing a reaction
residence time of 0.023 s for the iodine/lithium exchange. The
ClTMS quench reaction was allowed to stir for 30 min. before
adding aqueous saturated Na2CO3 and analyzing the organic layer
by GC. Conversion to the p-TMS derivative was determined by GC
analysis to be 98%.
Diethyl-(4-iodo-phenyl)-amine (10)22
1H NMR (CDCl3) d 1.14-1.17 (t, J = 7.4 Hz, 3H), 3.32–3.36 (q,
J = 7.5 Hz, 2H), 6.47–6.49 (d, J = 9.2 Hz, 2H), 7.45–7.47 (d,
J = 9.1 Hz, 2H). 13C NMR (CDCl3) d 12.6, 44.5, 75.7, 114.0, 137.9,
147.3.5
Preparation of N-(4-Iodo-phenyl)-acetamide (11) via N-
iodosuccinimide (NIS)5
To a clean dry flask equipped with a stir bar was added cyclo-
hexane (4.5 mL), acetanilide (0.68 g, 5.0 mmol), NIS (1.23 g,
5.5 mmol) and water (0.1 mL, 5.5 mmol).27 The reaction was held
at 60 °C for 24 h. The reaction mixture was then transferred to a
separatory funnel with the aid of MTBE (2–3 mL) and water
(3 mL). The organic layer was separated and washed with aqueous
saturated sodium bisufite and brine, dried over sodium sulfate and
concentrated in vacuo to provide crude product. The product was
triturated with toluene to afford 95% pure material (0.59 g; 45%).
The product was further purified by recrystallization from toluene
to afford analytically pure material. mp = 182–183 °C; 1H NMR
(CDCl3) d 1.62 (s, 1H), 2.16 (s, 3H), 7.27–7.29 (d, J = 8.6 Hz, 2H),
7.59–7.61 (d, J = 8.6 Hz, 2H). 13C NMR (CDCl3) d 24.8, 87.6, 121.7,
137.7, 138.0, 168.4.
Utilizing conditions established above for the X/Li exchange
in a continuous fashion, a second S3T1 Synthetron™ reactor
was coupled to the exit stream of the first reactor and chilled
to 6 °C with a circulating chiller. A 1.5 M solution of benzophe-
none in cyclohexane (containing 2 mL of THF) was prepared
and introduced to the second reaction at
a flow rate of
100 mL/min (utilizing a Buchi pump, Model C-610). This resulted
in essentially a 1:1:1 ratio of n-BuLi/p-IDMA/benzophenone. A
combined flow rate of 400 mL/min in the second reactor pro-
vided a residence time of 0.017 s for the nucleophilic addition
step. The exit stream from the second reactor was directed into
a flask containing 50 mL of brine. The biphasic-quenched reac-
tion mixture was transferred to a separatory funnel where the
aqueous layer was separated and back-extracted with 20 mL of
MTBE. The combined organic layers were washed with brine,
dried over sodium sulfate, and concentrated in vacuo to provide
a viscous oil. Overnight trituration with hexanes at 5 °C and fil-
tration afforded >95% pure triarylcarbinol 12 (4.8 g: 63%, unop-
timized isolation), confirmed by GC–MS and TLC (Rf = 0.33;
80:20 hexanes/ethyl acetate).
(4-Dimethylamino-phenyl)-diphenyl-methanol (12) synthesis:
two pot halogen/lithium exchange/derivatization
Iodination
To a clean dry flask (250 mL) equipped with a large stir bar was
added cyclohexane (40 mL), DMA (1.21 mL, 10 mmol), solid iodine
(2.79 g, 11.0 mmol) and saturated sodium carbonate solution
(2.8 mL). To prevent formation of a gummy precipitate MTBE
(3.6 mL) and water (enough to dilute the carbonate phase to three
times its original volume) were also added. The reaction mixture
was allowed to stir at room temperature for 24 h. This produced
a product solution indicating a GC yield of 95% p-IDMA.
Acknowledgments
In situ halogen/lithium exchange/benzophenone derivatization
The aqueous layer from the iodinated product in the flask was
removed and the organic layer was washed with aqueous satu-
rated sodium bisulfite (25 mL) and brine (20 mL), dried over so-
dium sulfate (2.5 g) to provide a cyclohexane/MTBE solution of
the iodinated product. The dried organic phase was transferred
to a clean dry flask under a nitrogen atmosphere which was
placed in an ice bath. To this cooled solution n-BuLi (2 M in cyclo-
hexane, 5.5 mL; 11.0 mmol) was added dropwise. After 5 min. a
solution of benzophenone (1.7 M) in cyclohexane (5.9 mL;
10 mmol) was also added dropwise. The reaction was allowed
to stir for an additional 10 min. before being quenched with
water. The organic layer was separated and washed with aqueous
sodium carbonate and brine, dried over sodium sulfate and con-
centrated in vacuo to provide crude product which was triturated
with hexanes to afford pure 12 (1.21 g; 40%, unoptimized
isolation). Recorded GC data showed 68% overall conversion
to the triphenylcarbinol derivative. mp = 84.5–86.0 °C (Lit.
Support of this research was under the auspices of NSF, CHE
070021. Support of our preliminary studies was provided by the
Petroleum Research Fund, PRF 42090-B1. Additional support was
received from the Western Kentucky University Research Founda-
tion. Continual consultation with Dr. Jeffrey Raber, President of
KinetiChem, Inc., re Synthetron™ reactor parameters was greatly
appreciated. Also greatly appreciated were the initiating efforts
of Rebecca Sandlin.
References and notes
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2. Ganguly, N. C.; Barik, S. K.; Dutta, S. Synthesis 2010, 9, 1467.
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