Lanthanide triflate-catalyzed preparation of β,β- difluorohomopropargyl alcohols in aqueous media. Application to the synthesis of 4,4-difluoroisochromans

Article abstract of DOI:10.1021/jo0614588

An indium-mediated Barbier-type reaction of difluoropropargyl bromide with several aldehydes in aqueous media was enhanced by a catalytic amount of a lanthanide triflate (5 mol %). The reaction gave the corresponding β,β-difluorohomopropargyl alcohols wit

Full text of DOI:10.1021/jo0614588

used to make fluorinated isoquinolines3a-c and other medicinal
targets such as panomifene.3d By comparison, there are fewer
methodologies for the synthesis of 2 or 3. The reason for this
is the inherent difficulty of executing nucleophilic substitutions
on a CF2 group due to the electronic repulsion between the
fluorine atoms and the incoming nucleophile, or the facile
formation of carbenoid intermediates arising from R-elimination
of fluoride in the presence of metals (Scheme 1, bottom). Our
group has recently overcome the problem of nucleophilic
substitution on a difluoromethylene carbon using a functional-
ized difluoroallene acting as a CF2 cation equivalent.2b Both
hard and soft nucleophiles produced 2 under mild conditions
and good yields. Electrophilic substitution on 1 has also been
accomplished using a Mg(0)-promoted reductive debromometa-
lation without loss of fluorine to give gem-difluoropropargyl-
silanes or gem-difluoropropargylstannanes, which can then react
with an electrophile to yield 3.2a The latter approach was
employed to synthesize homopropargyl alcohol 3ea (R ) R′ )
Ph) in excellent yield; however, this reaction required stringent
conditions and therefore it is not amenable for large-scale
synthesis.
Lanthanide Triflate-Catalyzed Preparation of
â,â-Difluorohomopropargyl Alcohols in Aqueous
Media. Application to the Synthesis of
4,4-Difluoroisochromans
Satoru Arimitsu and Gerald B. Hammond*
Department of Chemistry, UniVersity of LouisVille, LouisVille,
Kentucky, 40292
gb.hammond@louisVille.edu
ReceiVed July 13, 2006
Another method to prepare homopropargyl alcohol 3 [E )
-CH(OH)R′] uses zinc,4 but this protocol requires anhydrous
conditions. A green chemistry alternative is the indium-mediated
Barbier-type reaction of 1 with aldehydes. We originally
reported this approach using difluoropropargyl bromide2c but
later found that this protocol could not be scaled up without
decreasing the yield of the resulting homopropargyl alcohol 3
and reliable reproducibility; sonicating the reaction mixture
shortened the reaction time, but it contributed to an increased
amount of dimer 4. We now wish to report a practical and
scalable indium-mediated preparation of â,â-difluorohomopro-
pargyl alcohol 3 using a lanthanide triflate as a Lewis acid
catalyst in predominantly aqueous media. This alcohol was
converted to 3,3-difluoro-1,7-diyne 6, which in turn underwent
a facile catalytic [2 + 2 + 2] alkyne cyclotrimerization that
yielded fluorinated isochromans 8 and 9.
An indium-mediated Barbier-type reaction of difluoroprop-
argyl bromide with several aldehydes in aqueous media was
enhanced by a catalytic amount of a lanthanide triflate (5
mol %). The reaction gave the corresponding â,â-difluoro-
homopropargyl alcohols with high regioselectivity. The [2
+ 2 + 2] alkyne cyclotrimerization of â,â-difluorohomopro-
pargyl alcohols with monosubstituted acetylenes produced
4,4-difluoroisochromans in good yields with moderate re-
gioselectivity.
Homopropargyl alcohols are versatile building blocks in
organic synthesis.1 In this regard, the placement of a gem-
difluoromethylene carbon on a propargylic position can modify
the stereoelectronic properties of the resulting alkyne, leading
to regioselective carbon-carbon bond formation (i.e., propargyl
allenyl) by judicious choice of reagents and conditions.2a
Furthermore, the resulting alkyne or allene constitutes powerful
cycloaddition partners, which, in the case of the difluoroprop-
argyl system, could lead to practical syntheses of fluorinated
cyclic or heterocyclic targets of biological interest. Currently,
the synthesis of fluorinated heterocycles is done on a case-by-
case basis. There are two possible fluorine locations around a
triple bond: externally, capping the terminal acetylenic carbon
using a CF3 or Rf group (Scheme 1, top), or internally, bonded
to the propargyl carbon (i.e., 2 or 3) (Scheme 1, bottom).
Externally substituted fluorinated acetylenes have been prepared
from fluoroiodoolefins or trifluorobromopropene and have been
First, we revisited the reaction between difluoropropargyl
bromide (1a) and benzaldehyde (5a) (Table 1) by examining
the effect of the solvent on the yield of the product. Altering
the ratio of THF and H2O did not produce significant differences
in the reaction results (Table 1, entries 1-4), but when
anhydrous THF was employed, the reaction did not occur at all
and only starting material 1a was observed in the 19F NMR
spectrum (Table 1, entry 5). In anhydrous DMF, the reaction
produced a complex mixture (Table 1, entry 6). Increasing the
number of equivalents of aldehyde 5a was not effective either
(Table 1, entries 7 and 8). Because lanthanide triflates are known
for their unique Lewis acid behavior and their tolerance to
(3) (a) Konno, T.; Chae, J.; Miyabe, T.; Ishihara, T. J. Org. Chem. 2005,
70, 10172-10174. For other examples, see: (b) Konno, T.; Chae, J.;
Ishihara, T.; Yamanaka, H. J. Org. Chem. 2004, 69, 8258-8265. (c) Konno,
T.; Chae, J.; Ishihara, T.; Yamanaka, H. Tetrahedron 2004, 60, 11695-
11700. (d) Konno, T.; Daitoh, T.; Noiri, A.; Chae, J.; Ishihara, T.;
Yamanaka, H. Org. Lett. 2004, 6, 933-936.
(4) (a) Audouard, C.; Barsukov, I.; Fawcett, J.; Griffith, G. A.; Percy, J.
M.; Pintat, S.; Smith, C. A. Chem. Commun. 2004, 1526-1527. (b)
Hanzawa, Y.; Inazawa, K.; Kon, A.; Aoki, H.; Kobayashi, Y. Tetrahedron
Lett. 1987, 28, 659-662.
(1) For recent examples, see: (a) Miranda, P. O.; Ramirez, M. A.; Martin,
V. S.; Padron, J. I. Org. Lett. 2006, 8, 1633-1636. (b) Miura, K.; Wang,
D.; Matsumoto, Y.; Hosomi, A. Org. Lett. 2005, 7, 503-505. (c) Wipf, P.;
Graham, T. H. J. Org. Chem. 2003, 68, 8798-8807. (d) Trost, B. M.; Rhee,
Y. H. J. Am. Chem. Soc. 2003, 125, 7482-7483.
(2) (a) For a review, see: Hammond, G. B. J. Fluorine Chem. 2006,
127, 476-488. (b) Xu, B.; Hammond, G. B. Angew. Chem., Int. Ed. 2005,
44, 7404-7407. (c) Wang, Z.; Hammond, G. B. J. Org. Chem. 2000, 65,
6547-6553.
10.1021/jo0614588 CCC: $33.50 © 2006 American Chemical Society
Published on Web 10/05/2006
J. Org. Chem. 2006, 71, 8665-8668
8665

SCHEME 1. Synthetic Approaches to Externally and Internally Substituted Acetylenes
TABLE 1. Optimization of the Reaction between 1a and
Benzaldehyde (5a)
TABLE 2. Indium-Mediated Barbier-Type Reaction of 1 with
Several Aldehydes in Aqueous Media
X
additive
yield (%)a
3aa:4
entry
R
R′
yield (%)a
entry
solvent
(equiv of 5a) (5 mol %)
1
2
3
4
5
TIPS (1a)
TES (1b)b
TMS (1c)c
Ph (5a)
Ph (5a)
Ph (5a)
68 (3aa) [9.8]d
72 (3ba) [17.3]d
41 (3ca) [26.5]d
55 (3da)
1
2
3
4
5
6
7
8
9
H2O/THF (4/1)
H2O/THF (1/1)
H2O/THF (1/4)
satdNH4Claq/THF (4/1)
THF
1.1
1.1
1.1
1.1
1.1
1.1
2.2
3.3
20:6
31:12
25:7
20:4
no reaction
complex mixture
29:8
n-hex (1d)b Ph (5a)
Ph (1e)b
TES (1b)b
Ph (5a)
35 (3ea)
DMF
6
7
8
4-Me-C6H4 (5b)
65 (3bb)
61 (3bc)
60 (3bd)
73 (3be)
62 (3bf)
H2O/THF (4/1)
H2O/THF (4/1)
H2O/THF (1/1)
4-MeO-C6H4 (5c)
3-MeO-C6H4 (5d)
2,4-(MeO)2-C6H3 (5e)
4-OH-C6H4 (5f)
36:4
1.1
Sc(OTf)3 42:4
9
10
11
12
13
14
15
16
17
10 H2O/THF (4/1)
1.1
Sc(OTf)3 68:7
3,5-(CH3O)2-4-OH-C6H2 (5g) 61 (3bg)
11
12
13
14
15
16
Er(OTf)3 64:7
Eu(OTf)3 78:8
Tb(OTg)3 76:10
Sm(OTf)3 48:9
Y(OTf)3 47:13
Ce(OTf)3 77:8
4-Cl-C6H4 (5h)
2-F-C6H4 (5i)
4-NO2-C6H4 (5j)
Et (5k)
(CH3)2CH (5l)
BzOCH2 (5m)
71 (3bh)
65 (3bi)
no reaction
52 (3bk)
69 (3bl)
65 (3bm)
a Yield was determined by 19F NMR.
a Isolated yield b The reaction was sonicated for 12 h. c The reaction
was sonicated for 6 h. d The value in the parentheses is the yield ratio of 3
and dimer 4 calculated by 19F NMR.
aqueous media,5 we decided to screen various triflates (Table
1, entries 9-16), all of which showed an increase in the yield
of the alcohol. Eu(OTf)3 was found to give the best results
(Table 1, entry 12), and therefore it was chosen for subsequent
studies.
Next, the effect of R in the reaction of 1 with benzaldehyde
(5a) (Table 2, entries 1-5) was investigated. The nature of this
substituent had a pronounced effect on the product yield: alkyl
and aryl substituents were less efficient than silyl groups, the
only exception being TMS. Triethylsilyl (TES) and triisopro-
pylsilyl (TIPS) substituents were selected for further studies
because these functionalities could serve as convenient synthetic
handles for future transformations. The majority of aldehyde
substrates tested produced â,â-difluorohomopropargyl alcohols
3 in good to very good yields (Table 2, entries 6-17). Notably,
aldehydes bearing free hydroxyl groups could be used without
protection (Table 2, entries 10 and 11), but the reaction with
reactive 4-nitroaldehyde 5j did not give the expected product,
and only starting material 1b was recovered (Table 2, entry 14).
We never observed the formation of allenyl alcohols during
these experiments. This is in marked contrast with similar
reactions employing nonfluorinated alkynes, where the size of
the substituent influences the allenyl-to-propargyl ratio.
(5) (a) Kobayashi, S.; Manabe, K. Acc. Chem. Res. 2002, 35, 209-217.
(b) Kobayashi, S.; Manabe, K. Pure Appl. Chem. 2000, 72, 1373-1380.
8666 J. Org. Chem., Vol. 71, No. 22, 2006

TABLE 3. Synthesis of Difluoroisochromanes via RhCl(PPh3)3
Catalyzed [2 + 2 + 2] Cyclization
yield (%)a
entry
R
solvent
8:9
1
2
CH2OH (7a)
toluene
EtOH
CH2Cl2
THF
31:59
48:47
42:47
41:50
29:69
39:55
0:0
15:68
14:47
19:20
0:15
FIGURE 1. Examples of biologically active isochroman derivatives.
3
4b
5
benzene
A six-membered transition state in which the indium complex
coordinates with the carbonyl oxygen of aldehydes has been in-
voked to explain the allenyl-propargyl regiocontrol in nonflu-
orinated systems.6 If our reaction had followed a similar six-
membered transition state pathway, then we should have ob-
served a difluoroallenyl alcohol. The fact that we did not observe
such a byproduct led us to ponder whether a radical pathway
was in effect, in which case, water would play a crucial role in
the generation of radical species.7 Further studies to probe the
reaction mechanism of this unusual regioselectivity are needed.
Despite that fact that isochromans are biologically interesting
compounds (Figure 1),8 to our knowledge, there have been no
reports on the preparation of partially fluorinated isochromans.
We decided to investigate the synthesis of 4,4-difluoroiso-
chromans 8 or 9 using a rhodium-catalyzed [2 + 2 + 2]
cyclotrimerization of 3,3-difluoro-1,7-diene 6 with monosub-
stituted acetylenes. The starting material 6 was easily prepared
in two steps from propargyl alcohol 3aa (eq 1).
6
7
8
9
10
11
n-hex (7b)
TMS (7c)
Ph (7d)
p-F-C6H4 (7e)
p-CF3-C6H4 (7b)
C6F5 (7g)
a Yield was determined by 19F NMR. b Recovered starting material (8%).
may imply that the regiochemistry of the reaction is controlled
by electronic rather than steric effects.
On the basis of the widely accepted mechanism of [2 + 2 + 2]
alkyne cyclotrimerizations,9 we proposed the pathway outlined in
Scheme 2 to explain the regioselectivity found in our experiments.
Initially, two triple bonds coordinate to the metal to give metal-
lacyclopentadiene Int-I through an oxidative coupling, followed
by a third triple bond insertion to the intermediate metallacy-
clopentadiene, and a final reductive elimination to yield products
8 and 9. The rationale for this regioselectivity can be traced to
the steric hindrance that exists between the metal ligands and
the substituent R of the third acetylene, and the electronic density
differences between C-a and C-b (see TS-A and TS-B in
Scheme 2). The electronic deficiency in C-a may be due to the
strong electron-withdrawing effect of fluorine, and therefore the
insertion of the third acetylene to the metallacyclopentadiene
would take place from the C-b side.10
In summary, we have investigated an environmentally friendly
and reliable synthesis of difluorohomopropargyl alcohols utilizing
indium and a catalytic amount of Eu(OTf)3. 3,3-Difluoro-1,7-
diene, prepared in two steps from â,â-difluorohomopropargyl
alcohol, reacted with monosubstituted acetylenes in the presence
of RhCl(PPh3)3 to produce the hitherto unknown 4,4-difluor-
oisochromans in moderate-to-good yields and regioselectivities.
Table 3 shows the optimization and scope of this methodol-
ogy. Of the solvents screened, benzene furnished the best ratio
of 8a-to-9a (Table 3, entry 5), and thus it was selected for the
cyclotrimerization of 6 with other alkynes 7. With the exception
of 7c (Table 3, entry 7), this cyclization yielded a mixture of
regioisomers 8 and 9 in moderate-to-good yields. When the
substituent R contained an electron-withdrawing group, the mass
balance of products 8 and 9 diminished (Table 3, entries 9-11),
possibly due to the formation of complex fluorinated byproducts,
visible in the 19F NMR spectrum of the reaction mixture. In all
cases examined, the dominant product was the regioisomer 9,
even though both alkyne groups in 6 are terminal; these results
Experimental Section
Synthesis of 2,2-Difluoro-1-phenyl-4-triethylsilylbut-3-yn-1-
ol (3ba). To a flask were added indium powder (2.0 mmol, 1.0
equiv) and Eu(OTf)3 (0.1 mmol, 5 mol %), then triethylsilyl
difluoropropargyl bromide (1b) (2.0 mmol) and benzaldehyde (5a)
(2.2 mmol, 1.1 equiv) with rinsing by THF/H2O solution (1/4) (6.6
mL, 0.3 M). The reaction was sonicated at 40 °C for 12 h. The
reaction was quenched with 10% HCl (10 mL) and extracted by
(6) (a) Alcaide, B.; Almendros, P.; Mart, T. Angew. Chem., Int. Ed. 2006,
45, 4501-4504. (b) Miao, W.; Chung, L. W.; Wu, Y. D. J. Am. Chem.
Soc. 2004, 126, 13326-13334. (c) Lin, M. J.; Loh, T. P. J. Am. Chem.
Soc. 2003, 125, 13042-13043. (d) Yi, X. H.; Meng, Y.; Hua, X. G.; Li, C.
J. J. Org. Chem. 1998, 63, 7472-7480. (e) Miao, W.; Lu, W.; Chan, T. H.
J. Am. Chem. Soc. 2003, 125, 2412-2413.
(7) (a) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Tetrahedron 2004,
60, 4227-4235. (b) Miyabe, H.; Naito, T. Org. Biomol. Chem. 2004, 2,
1267-1270. (c) Miyabe, H.; Ueda, M.; Nishimura, A.; Naito, T. Org. Lett.
2002, 4, 131-134. (d) Miyabe, H.; Nishimura, A.; Ueda, M.; Naito, T.
Chem. Commun. 2002, 1454-1455.
(8) (a) Liu, J.; Birzin, E. T.; Chan, W.; Yang, Y. T.; Pai, L.-Y.; DaSilva,
C.; Hayes, E. C.; Mosley, R. T.; DiNinno, F.; Rohrer, S. P.; Schaeffer, J.
M.; Hammond, M. L. Bioorg. Med. Chem. Lett. 2005, 15, 715-518. (b)
Ennis, M. D.; Ghazal, N. B.; Hoffman, R. L.; Smith, M. W.; Schlachter, S.
K.; Lawson, C. F.; Im, W. B.; Pregenzer, J. F.; Svensson, K. A.; Lewis, R.
A.; Hall, E. D.; Sutter, D. M.; Harris, L. T.; McCall, R. B. J. Med. Chem.
1998, 41, 2180-2183.
(9) For the theoretical study related to [2 + 2 + 2] cycloaddition, see:
(a) Dahy, A. A.; Suresh, C. H.; Koga, N. Bull. Chem. Soc. Jpn. 2005, 78,
792-803. (b) Dahy, A. A.; Koga, N. Bull. Chem. Soc. Jpn. 2005, 78, 781-
791. (c) Kirchner, K.; Calhorda, M. J.; Schmid, R.; Veiros, L. F. J. Am.
Chem. Soc. 2003, 125, 11721-11729.
(10) (a) Yamamoto, Y.; Kinpara, K.; Saigoku, T.; Takagishi, H.; Okuda,
S.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 605-613. (b)
Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005,
127, 9625-9631.
J. Org. Chem, Vol. 71, No. 22, 2006 8667

SCHEME 2. Plausible Reaction Mechanism for [2 + 2 + 2] Cyclization Leading to Difluoroisochromans
ethyl acetate (10 mL × 3), and the combined organic layers were
washed with brine and dried over anhydrous Na2SO4. After
evaporation of the solvent, the residue was purified by silica gel
with EtOAc/hexane (1/40) to afford 3ba (388 mg, 72%). 1H NMR
(CDCl3) δ: 0.62 (q, J ) 8.0 Hz, 6H), 0.96 (t, J ) 8.0 Hz, 9H),
2.60 (d-like, 1H), 4.93-4.97 (m, 1H), 7.37-7.39 (m, 3H), 7.50-
7.52 (m, 2H); 19F NMR (CDCl3) δ: -93.50 (dd, J ) 267.7, 6.6
Hz, 1F), -95.23 (dd, J ) 274.4, 9.9 Hz, 1F); 13C NMR (CDCl3)
δ: 4.0, 7.5, 76.6 (t, J ) 29.3 Hz), 95.1, 95.6 (t, J ) 37.7 Hz),
) 280.5 Hz, 1F); 13C NMR (CDCl3) δ: 56.8, 74.5 (t, J ) 38.9
Hz), 75.8, 77.5, 78.1, 80.9 (t, J ) 29.2 Hz), 112.1 (t, J ) 238.5
Hz), 128.4, 128.8, 129.5, 132.5; IR (neat) cm-1: 3293, 3066, 3035,
2900, 2358, 2134, 1961, 1456, 1338, 1176, 1076; MS m/z (%):
165 (13), 145 (100), 115 (34), 105 (92), 92 (3); Anal. Calcd: C,
70.90; H, 4.58. Found: C, 70.35; H, 4.35
Synthesis of 4,4-Difluoroisochromans 8a and 9a. Into a flask
were added RhCl(PPh3)3 (0.025 mmol, 5.0 mol %), the starting
material (6) (0.5 mmol, 1.0 equiv), and also propargyl alcohol (7a)
(2.5 mmol, 5.0 equiv) in benzene (0.01 M), and the reaction mixture
was heated to reflux for 6 h. After the consumption of starting
material (6) (as monitored by TLC or GC-MS), the solvent was
removed by rotary evaporation, and the corresponding products 8a
(30 mg, 22%) and 9a (82 mg, 60%) were isolated by the silica gel
chromatography with EtOAc/hexane (1/4).
113.3 (t, J ) 238.5 Hz), 128.1, 128.4, 129.3, 135.4; IR (neat) cm-1
:
3446, 2958, 2877, 2360, 2187, 1716; MS m/z (%): 243 (14), 187
(11), 109 (12), 91 (15), 81 (100); Anal. Calcd: C, 64.83; H, 7.48.
Found: C, 64.93; H, 7.57.
Preparation of 3,3-Difluoro-4-phenyl-4-(2-propynyloxy)-1-
butyne (6). To a suspension of NaH (5.75 mmol, 1.15 equiv) in
THF (50 mL, 0.1 M) was slowly added 2,2-difluoro-1-phenyl-4-
triisopropylsilylbut-3-yn-1-ol (3aa) (5.0 mmol, 1.0 equiv) at 0 °C
for 30 min, then the propargyl bromide (5.5 mmol, 1.1 equiv) was
added into the reaction mixture at 0 °C, and the reaction mixture
was stirred at room temperature for 24 h. After the reaction mixture
was quenched by 10% HCl and extracted with Et2O, the product
was obtained in 75% by simple short silica gel column purification.
Desilylation was performed by the following procedure. First, a
solution of AcOH (2.2 equiv) and TBAF (2.86 equiv) in THF (12
mL) was mixed together at room temperature for 30 min, then the
THF solution (12 mL) of the prepared starting material was added
at room temperature, and the mixture was stirred at room temper-
ature for 5 h. The reaction was quenched and extracted by the same
method described above. The final product 6 (776 mg, 94%) was
isolated by silica gel column chromatography with EtOAc/hexane
4,4-Difluoro-7-hydroxylmethyl-3-phenylisochroman (9a). 1H
NMR (CDCl3) δ: 1.73 (1H), 4.68 (2H), 4.79 (dd, J ) 20.0, 2.0
Hz, 1H), 4.92 (dd, J ) 15.0, 4.0 Hz, 1H), 5.00 (dd, J ) 15.5, 1.0
Hz, 1H), 7.12 (1H), 7.31-7.37 (m, 4H), 7.46 (d, J ) 7.0 Hz, 2H),
7.66 (d, J ) 8.0 Hz, 1H); 19F NMR (CDCl3) δ: -94.23 (dd, J )
271.1, 23.1 Hz, 1F), -107.90 (d, J ) 272.5 Hz, 1F); 13C NMR
(CDCl3) δ: 64.9, 68.8, 80.0 (dd, J ) 29.1, 26.0 Hz), 114.2 (dd, J
) 247.6, 239.9 Hz), 121.9, 126.18, 126.22, 128.1, 128.4, 129.0,
129.7 (t, J ) 25.7 Hz), 133.7, 136.4, 143.7; MS m/z (%): 255 (4),
198 (6), 170 (100), 141 (7), 122 (5), 105 (9).
Acknowledgment. We are grateful to the National Science
Foundation (CHE-0513483) for financial support.
Supporting Information Available: Analytical and spectro-
scopic data for 3ca, 3da, 3bb-3bm, 8a, 8b, 8d-8f, and 9b, 9d-
9g. This material is available free of charge via the Internet at
http://pubs.acs.org.
1
(1/40). H NMR (CDCl3) δ: 2.48 (1H), 2.81 (t, J ) 5.0 Hz, 1H),
4.10 (dd, J ) 16.0, 2.0 Hz, 1H), 4.38 (dd, J ) 16.0, 2.0 Hz, 1H),
4.90 (t, J ) 9.3 Hz, 1H), 7.41-7.42 (m, 3H), 7.48-7.49 (m, 2H);
19F NMR (CDCl3) δ: -91.89 (d, J ) 277.2 Hz, 1F), -94.39 (d, J
JO0614588
8668 J. Org. Chem., Vol. 71, No. 22, 2006