Solvent-free methallylboration of ketones accelerated by tert-alcohols

Article abstract of DOI:10.1021/jo4006574

A solvent- and metal-free process has been developed for the direct methallylboration of ketones employing the stable B-methallylborinane 1, which was accelerated by tertiary alcohols. In the presence of 2.0 equiv of readily available tertiary alcohols such as tert-amyl alcohol, the methallylation products were prepared at room temperature in excellent yields. The salient features of the described process include simple operation, high efficiency, and mild reaction conditions.

Full text of DOI:10.1021/jo4006574

Note
pubs.acs.org/joc
Solvent-Free Methallylboration of Ketones Accelerated
by tert-Alcohols
Yongda Zhang,* Ning Li, Navneet Goyal, Guisheng Li, Heewon Lee, Bruce Z. Lu,
and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, Connecticut 06877-0368,
United States
S
* Supporting Information
ABSTRACT: A solvent- and metal-free process has been
developed for the direct methallylboration of ketones employ-
ing the stable B-methallylborinane 1, which was accelerated by
tertiary alcohols. In the presence of 2.0 equiv of readily available
tertiary alcohols such as tert-amyl alcohol, the methallylation
products were prepared at room temperature in excellent yields.
The salient features of the described process include simple
operation, high efficiency, and mild reaction conditions.
ver the past two decades, numerous efforts have been
reagent 1 is a colorless liquid that is easily synthesized, purified,
Odirected toward the synthesis of tertiary homoallylic and stored in the freezer for months without decomposition.18
alcohols via the allylation of ketones.1 In particular, allyl
Our work commenced with the methallylation of 2-methoxy-
acetophenone (2) by simply mixing with 1 under nitrogen
under neat conditions. In the presence of 1.5 equiv of 1, the
methallylboration is sluggish at 23 °C and gave 27% and 51%
conversion after 6 and 22 h, respectively (Scheme 1).
organoboron reagents have been extensively employed for this
process, but typically, a metal catalyst is required to affect the
allylboration (In,2−4 Cu,5 Ir,6 Zn,7 Ni8). Alternatively, the direct
metal-free allylboration of ketones represents the most simple,
convenient, and economical method for the synthesis of tertiary
homoallylic alcohols.9 However, to date, this type of reaction
manifold has not been well explored.10 Ketones bearing a
coordinating functional group that can serve as an activating
group, such as a hydroxyl group, have been reported to react
efficiently in the metal-free allylboration.11 However, simple
ketones such as acetophenone give poor reaction rates.12
Furthermore, these reactions utilize allyldiisopropoxyborate which
is a hydrolytically unstable reagent and, therefore, can be difficult to
handle. The sensitivity of this reagent toward hydrolysis has
prevented its further application especially on industrial scale. To
circumvent this issue, more stable allylboron reagents such as
allyltrifluoroborates13,14 and allyl dioxazaborolidines15 have been
employed, but strong Brønsted acids such as TsOH and
CF3CO2H were essential to affect the desired transformation.
Diminished efficiency was observed when weaker acids such as
PhOH were applied using these reagents. Considering the
importance of the allylation of ketones, it is highly desirable to
further investigate the direct metal-free allylboration of ketones. As
a part of our continuous research program directed at the
methallylation of ketones,16 herein, we report our research progress
regarding the development of a mild solvent- and metal-free
process for the methallylboration of ketones, which we have found
is accelerated by tertiary alcohols.17
Scheme 1. Methallylation of 2-Methoxyacetophenone 2
and 1
On the basis of the systematic studies from Brown and co-
workers on the allylboration of aldehydes,19 we envisioned that
the reaction rate could be modulated by changing the availability
of the lone pairs of electrons on the oxygen atom attached to
boron to donate to the vacant p-orbital on boron (n→p). Because
allylborations proceed through a closed chairlike transition state,20
organoboron reagents with diminished n→p donation are more
reactive in the allylboration due to the enhanced Lewis acidity at the
boron atom. Furthermore, we hypothesized that a hydrogen-
bonding interaction between an appropriate donor and the oxygen
atom of the organoboron reagent could have the same effect.
Therefore, we explored the use of a suitable alcohol additive that
could enable the direct methallylboration to occur in a mild,
effective, and practical manner. To this end, a variety of alcohols
were investigated for the methallylboration of 2′-acetonaphthone 4.
To develop a practical method for the direct metal-free
methallylation of ketones, B-2-(2-methylallyl)-1,3,2-dioxabor-
inane (1) was chosen as a methallyl-transfer reagent for further
investigation because of its excellent stability. Methallylboron
Received: March 28, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 1. Alcohol effect on the methallylation of 2′-acetonaphthone 4. All reactions were run at 23 °C with 4 (1 mmol), 1.5 equiv of 1, and 2 equiv
of alcohols or water under nitrogen.
Figure 2. Effect of amount of tert-amylOH on the methallylation of 2-methoxyacetophenone 2. All reactions were run with 1.5 equiv of 1 and
variable amounts of tert-amylOH at 23 °C under nitrogen.
Our results clearly indicated that the addition of different
alcohols resulted in variable reaction rates (Figure 1). The use
of primary or secondary alcohols gave reduced reaction rate.
11B NMR studies indicated that borinane 1 did not undergo
protodeboronation immediately in the presence of MeOH, but
different borate species were observed. We speculated that
primary and secondary alcohols (i.e., MeOH, EtOH, 2-PrOH)
could undergo ligand exchange with the cyclic alcohol of
reagent 1 and form an inactive borate complex. Without
addition of any alcohol, the reaction gave 90% conversion
after 5 h. In comparison, in the presence of 2.0 equiv of bulky
tertiary alcohols (i.e., as t-BuOH or tert-amylOH), all reactions
became faster and full conversions were achieved after 5 h.
Additionally, the use of 2.0 equiv of phenol as an additive gave
complete conversion in only 4 h. However, in the presence of
2.0 equiv of water, the reaction was again slow. Based on the
above results, we chose to further investigate the use of tert-
amylOH in the methallylation reaction due to the convenience
of this reagent relative to t-BuOH.21
To further illustrate the effect of tert-amylOH on the
methallylboration of ketones, we investigated the reaction rate
with sterically hindered 2-methoxyacetophenone 2 in the
presence of variable amounts of tert-amylOH (Figure 2).
Without tert-amylOH, the reaction was slow and gave only 51%
conversion after 22 h at 23 °C as mentioned before. Clearly, the
addition of tert-amyl alcohol led to faster reaction, and our
B
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
Figure 3. Effect of reaction temperature on the methallylation of 2-methoxyacetophenone 2. All of the reactions were run with 1.5 equiv of 1 and
2.0 equiv of tert-amylOH under nitrogen.
studies showed that the optimal amount of tert-amylOH was
1.0−3.5 equiv relative to 2. The addition of a large excess of
tert-amylOH (5.0 equiv) was observed to retard the reaction
rate, and only 90% conversion was obtained after 22 h.
borinane 1 (Table1, entries 8 and 9). Current reaction
conditions also tolerated a variety of acid-sensitive function
groups such as acetal, THP, and Boc (Table 1, entries 9, 11, and
12, respectively). It is well-known that function groups such as
phenyl acetate are not compatible with organometallic reagents
such as Grignard reagents. Under our conditions, the product 21
with an acetate moiety was isolated in 94% yield (Table 1, entry
10). Excellent yields were observed when heteroaryl ketones such
as 26 and 28 were used (Table 1, entries 13 and 14). When β-
keto acid 30 was applied, the corresponding product 31 was
isolated in 89% yield after overnight in the absence of tert-
amylOH, which indicated that the acid functional group could
promote the methallylation (Table 1, entry 15). In the case of β-
hydroxy ketone 32, the reaction proceeded smoothly to give the
product 33 in 85% yield (Table 1, entry 16).22 As discussed
before, the methallylation reaction was accelerated by phenol.
When cyclic alkyl ketone 38 containing a phenol function group
was used, the allylboration gave the product 39 in 82% yield
without the addition of tert-amylOH (Table 1, entry 19). When
the phenol was protected as an acetate, no reaction was observed
without tert-amylOH (Table 1, entry 20).
To further demonstrate the synthetic utility of the current
method, the methallylation of ketone 32 has been performed
on 10 g scale. After the reaction went to completion at 30 °C
overnight, the product 33 was precipitated from the reaction
mixture by the addition of water and isolated directly by
filtration as a white solid in 80% yield.
In summary, a facile and efficient solvent- and metal-free
process has been developed for the direct methallylboration of
ketones, which was accelerated by tertiary alcohols such as tert-
amyl alcohol. Under our optimized reaction conditions, a wide
array of ketones with acid- or base-sensitive functional groups
such as THP, Boc and OAc underwent direct methallylboration
smoothly. The methallylation products were easily isolated in
high yields without tedious workup. The salient features of this
process include simple operation, high efficiency, and mild
reaction conditions, which should make it appealing for
practical applications especially when strong acids and bases
Moreover, we also investigated the temperature effect on the
methallylboration of ketones. Not surprisingly, a higher
temperature gave a faster reaction (Figure 3). In all cases, full
conversion with 2 was observed with 1.5 equiv of 1 after
overnight. The reaction time was shortened to 6 h at 80 °C,
and the product 3 was isolated in 96% isolated yield. At 40 °C,
the reaction was complete after 16 h and gave the product 3 in
95% isolated yield. In comparison, the reaction at 40 °C
without tert-amylOH gave the product 3 with 76% isolated
yield after 16 h. While increased reaction temperature allows for
a reduction in reaction time for the methallylboration and can be
used for simple ketones, we wanted a methallylboration procedure
that would be compatible with more elaborate, highly function-
alized ketones that could be sensitive to high reaction temper-
atures; therefore, we decided to further investigate this process
under ambient conditions (23 °C).
The scope of the current method for the methallylation of
ketones was next investigated employing a variety of ketones
including aliphatic ketones, aromatic ketones, and hetero-
aromatic ketones with diverse functional groups (Table 1). All
of the reactions were run overnight at 23 °C in the presence of
2.0 equiv of tert-amylOH. In all cases, the crude methallylation
products were purified by passing through a short silica gel
column without tedious workup. Typically, good to excellent
yields were obtained. When methyl ketones 2, 4, 6, and 8
(Table 1, entries 1−4) were used, the corresponding products
3, 5, 7, and 9 were isolated in greater than 90% yield. The
reaction tolerated bromo and cyano functional groups at the
α-position of the ketones (entries 5 and 6, respectively)
affording the desired methallylation products in quantitative
yields. No elimination was observed when β-chloro ketone 14
was applied (Table 1, entry 7). The corresponding product 15
was isolated in 89% yield. In the presence of tert-amylOH, even
less reactive alkyl ketones 16 and 18 reacted smoothly with
C
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
have to be avoided to achieve highly selective methallylation
reactions.
Table 1. Methallylation of Ketones with Borinane 1
EXPERIMENTAL SECTION
■
General Methods. All reactions were run in an oven-dried flask
under nitrogen. Unless otherwise noted, reagents were commercially
available and were used without purification. HPLC conditions for
reaction monitoring and quantitation: column Halo C8, 4.6 × 150 mm,
2.7 μm particle size, column temperature at 25 °C, mobile phase A
(0.2% H3PO4 in water), mobile phase B (acetonitrile), flow rate
1.2 mL min−1, gradient program 30% B to 70% B in 6 min, to 85% B
in 1 min, to 98% B in 0.5 min, hold at 98% B for 4.5 min, λ = 220 nm,
flow rate 1.0 mL min−1. The samples for HPLC were diluted with
MeOH. Chemical shifts are reported in δ (ppm) relative to TMS in
CDCl3 as internal standard (1H NMR) or the residual CHCl3 signal
13
(
C NMR).
Synthesis of B-2-(2-Methylallyl)-1,3,2-dioxaborinane 1.
To a dry three-necked flask were charged Mg turnings (12.0 g, 497
mmol) under argon. THF (350.0 mL) was added followed by addition
of 1.2 M DIBAL-H in heptane (8.28 mL, 0.03 equiv). The solution
was allowed to sit for 1 h and became gray. 3-Chloro-2-methylprop-1-
ene (30 g, 331.3 mmol) was added to the flask while the temperature
was maintained between 20 and 25 °C. After the complete addition,
the mixture was stirred for 2 h at that temperature. The solution was
titrated with bipyridine as indicator. The concentration is about
0.62 M.
To a dry flask were charged the Grignard reagent (248 mmol, 400 mL)
prepared above and MTBE (200 mL). After the mixture was
cooled to −60 °C (dry ice bath), trimethyl boronate (25.8 g,
248 mmol, 1.0 equiv) was added while the internal temperature was
maintained below −60 °C. The resulting solution was stirred at −50 to
−60 °C for 30 min and then slowly warmed to 0 °C over 30 min. AcCl
(17.5 g, 223.2 mmol, 0.900 equiv) was charged while the temperature
was controlled below 5 °C. After that, the reaction mixture was
allowed to warm to room temperature and then propane-1,3-diol
(17.0 g, 223 mmol, 0.900 equiv) was charged into the flask in one
portion. The resulting reaction mixture was stirred at 23 °C overnight.
1,4-Dioxane (32.78 g, 372 mmol, 1.50 equiv) was added to the
mixture. After 2 h, the solid was filtered off through a Celite pad, which
was washed with MTBE (200 mL). The residue on removal of the
solvent was diluted with hexane (100 mL). The solid was removed by
filtration. The filtrate was concentrated and purified by passing a short
silica gel column with 10% MTBE in hexane as elute or by distillation
under vacuum to give the product 1 as a colorless liquid (34.8 g, 75%):
1H NMR (400 MHz, CDCl3), δ 4.64 (d, 1H, J = 0.84 Hz), 4.58
(d, 1H, J = 0.84 Hz), 4.0−3.98 (m, 4H), 1.97−1.91 (m, 2H), 1.75 (bs,
3H), 1.63 (bs, 2H); 13C NMR (100 MHz, CDCl3) δ 144.2, 109.3, 61.8,
50.2, 27.3, 24.4; HRMS (TOF-MS, electrospray negative ionization) m/z
calcd for C15H10BO4− [C4H9BO2 + HCO2]− 145.06776, found 145.0676.
General Procedure for Methallylation of Ketones. To a dry
flask were charged ketone (1.0 mmol), 1 (1.5 equiv), and tert-amylOH
(2.0 equiv) under nitrogen. The resulting mixture was stirred under
nitrogen at room temperature for overnight. Purification of the
reaction mixture by column chromatography on silica gel gave
analytically pure product.
2-(2-Methoxyphenyl)-4-methylpent-4-en-2-ol 3. The general
procedure above was followed using 1-(2-methoxyphenyl)ethanone 2
(150.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol
(176.3 mg, 2.0 mmol). After being allowed to sit overnight, the reaction
mixture was purified by column chromatography on silica gel (eluting with
5% EtOAc/hexanes) to afford the product 3 as a liquid (191.8 mg, 93%):
1H NMR (400 MHz, CDCl3), δ 7.37 (dd, 1H, J = 1.7, 7.7 Hz), 7.23 (m,
1H), 3.94−6.88 (m, 2H), 4.81 (bs, 1H), 4.67 (bs, 1H), 3.89 (s, 3H), 3.68
(s, 1H), 2.88 (d, 1H, J = 13.1 Hz), 2.54 (d, 1H, J = 9.9 Hz), 1.60 (s, 3H),
a
All of the reactions were run with ketones (1 mmol), 1.5 equiv of 1, and
b
2.0 equiv of tert-amylOH at 23 °C unless noted elsewhere. Isolated
yields after chromatography on silica gel. No tert-amylOH was added.
c
D
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
1.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 156.7, 143.2, 135.1, 128.2,
126.7, 120.8, 114.9, 111.1, 73.8, 55.2, 49.7, 27.3, 23.9; HRMS (ES pos) m/z
calcd for C13H17O+ (M − H2O + H+) 189.1274, found 189.1265.
4-Methyl-2-(naphthalen-2-yl)pent-4-en-2-ol 5.23 The general
procedure above was followed, using 1-(naphthalen-2-yl)ethanone 4
(170.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol
(176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 5 as a solid
(215.0 mg, 95%): mp 46−47 °C; 1H NMR (400 MHz, CDCl3), δ 7.93
(s, 1H), 7.81 (t, 3H, J = 8.7 Hz), 7.53 (d, 1H, J = 8.8 Hz), 7.42−7.48
(m, 2H), 4.89 (s, 1H), 4.77 (s, 1H), 2.76 (d, 1H, J = 13.0 Hz), 2.60 (d,
1H, J = 13.2 Hz), 2.48 (s, 1H), 1.63 (s, 3H), 1.37 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 145.2, 142.5, 133.2, 132.2, 128.2, 127.7, 127.5,
126.0, 125.6, 123.8, 123.0, 115.8, 73.4, 51.8, 30.8, 24.3; HRMS (ES pos)
1-Chloro-5-methyl-3-phenylhex-5-en-3-ol 15. The general proce-
dure above was followed using 3-chloro-1-phenylpropan-1-one 14
(168.6 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol
(176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 15 as a liquid
(200.0 mg, 89%): 1H NMR (400 MHz, CDCl3), δ 7.30−7.40 (m, 4H),
7.21−7.26 (m, 1H), 4.92 (s, 1H), 4.77 (s, 1H), 3.53−3.60 (m, 1H),
3.10−3.17 (m, 1H), 2.67 (d, 1H, J = 13.7 Hz), 2.54 (d, 1H, J = 13.7
Hz), 2.52 (s, 1H), 2.24−2.40 (m, 2H), 1.29 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.5, 141.7, 128.3, 126.9, 125.1, 116.5, 74.5, 51.5,
46.4, 40.2, 24.3; HRMS (ES pos) m/z calcd for C13H21ClNO+ (M +
+
NH4 ) 242.1306, found 242.1297.
1-(2-Methylallyl)-4-phenylcyclohexanol 17. The general proce-
dure above was followed using 4-phenylcyclohexanone 16 (174.2 mg,
1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol (176.3 mg,
2.0 mmol). After being allowed to sit overnight, the reaction mixture
was purified by column chromatography on silica gel (eluting with 5%
EtOAc/hexanes) to afford the product 17 as a liquid (207.3 mg, 90%):
1H NMR (400 MHz, CDCl3), δ 7.31−7.16 (m, 5H), 4.96 (bs, 1H),
4.79 (bs, 1H), 2.50−2.44 (m, 1H), 2.22 (bs, 2H), 1.92−1.71 (m, 8H),
1.58−1.50 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 147.3, 142.4, 128.3,
126.9, 126.0, 114.9, 70.0, 51.7, 44.0, 37.8, 29.4, 25.5; HRMS (ES pos) m/z
calcd for C16H26NO+ (M + NH4+) 248.2009, found 248.2006.
+
m/z calcd for C16H17 (M − H2O + H+) 209.1325, found 209.1318.
2-(2,5-Dimethoxyphenyl)-4-methylpent-4-en-2-ol 7. The general
procedure above was followed using 1-(2,5-dimethoxyphenyl)-
ethanone 6 (18.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and
tert-amyl alcohol (176.3 mg, 2.0 mmol). After being allowed to sit
overnight, the reaction mixture was purified by column chromatog-
raphy on silica gel (eluting with 5% EtOAc/hexanes) to afford the
product 7 as a solid (198.2 mg, 90%): mp 45−46 °C; 1H NMR
(400 MHz, CDCl3), δ 6.99 (d, 1H, J = 3.1 Hz), 6.81 (d, 1H, J = 8.8
Hz), 6.75−6.72 (m, 1H), 4.82 (bs, 1H), 4.68 (bs, 1H), 3.85 (s, 3H),
3.77 (s, 3H), 3.66 (s, 1H), 2.90 (d, 1H, J = 13.1 Hz), 2.52 (d, 1H, J =
13.2 Hz), 1.58 (s, 3H), 1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
153.6, 150.9, 143.2, 136.5, 114.9, 113.7, 111.9, 111.6, 73.7, 55.7, 49.6,
8-(2-Methylallyl)-1,4-dioxaspiro[4.5]decan-8-ol 19. The general
procedure above was followed using 1,4-dioxaspiro[4.5]decan-8-one
18 (156.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl
alcohol (176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 19 as a liquid
(191.2 mg, 90%): 1H NMR (400 MHz, CDCl3), δ 4.94 (bs, 1H), 4.77
(bs, 1H), 3.98−3.91 (m, 4H), 2.21 (bs, 2H), 1.95−1.90 (m, 2H), 1.84
(s, 3H), 1.72−1.56 (m, 7H); 13C NMR (100 MHz, CDCl3) δ 142.4,
115.0, 108.8, 70.0, 64.3, 64.2, 49.9, 35.2, 30.6, 25.3; HRMS (ES pos)
m/z calcd for C12H19O2+ (M − H2O + H+) 195.1380, found 195.1375.
4-(2-Hydroxy-4-methylpent-4-en-2-yl)phenyl acetate 21. The
general procedure above was followed using 4-acetylphenyl acetate
20 (178.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl
alcohol (176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 21 as a liquid
(220.2 mg, 94%): 1H NMR (400 MHz, CDCl3), δ 7.45 (dd, 2H, J = 4.0,
8.0 Hz), 7.04 (dd, 2H, J = 4.0, 8.0 Hz), 4.91 (s, 1H), 4.75 (s, 1H), 2.62 (d,
1H, J = 13.4 Hz), 2.51 (d, 1H, J = 13.4 Hz), 2.30 (s, 3H), 1.56 (s, 3H),
1.44 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 169.5, 149.3, 145.6, 142.4,
126.0, 121.0, 115.8, 73.1, 52.0, 30.6, 24.3, 21.2; HRMS (ES pos) m/z
calcd for C14H22NO3+ (M + NH4+) 252.1594, found 252.1585.
4-Methyl-2-(4-(tetrahydro-2H-pyran-2-yloxy)phenyl)pent-4-en-2-
ol 23. The general procedure above was followed using 1-(4-
(tetrahydro-2H-pyran-2-yloxy)phenyl)ethanone 22 (220.3 mg, 1.0
mmol), 1 (1.5 mmol, 1.5 equiv) and tert-amyl alcohol (176.3 mg, 2.0
mmol). After being allowed to sit overnight, the reaction mixture was
purified by column chromatography on silica gel (eluting with 5%
EtOAc/hexanes) to afford the product 23 as a solid (251.5 mg, 91%):
mp 38−39 °C; 1H NMR (400 MHz, CDCl3), δ 7.34 (dd, 2H, J = 4.0,
8.0 Hz), 7.00 (dd, 2H, J = 4.0, 8.0 Hz), 5.39 (s, 1H), 4.89 (s, 1H), 4.74
(s, 1H), 3.92 (m, 1H), 3.62 (m, 1H), 2.54 (dd, 2H, J = 1.2, 16 Hz),
2.25 (s, 1H), 2.0 (m, 1H), 1.87−1.84 (m, 2H), 1.68−1.63 (m, 3H), 1.54
(s, 3H), 1.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.7, 142.7,
141.1, 125.9, 115.9, 115.5, 96.5, 73.0, 62.1, 52.1, 30.6, 25.2, 24.3, 18.9;
HRMS (ES pos) m/z calcd for C19H31N2O3+ (M + CH3CN + NH4+)
335.2329, found 335.2315.
+
27.4, 23.9; HRMS (ES pos) m/z calcd for C14H19O2 (M − H2O +
H+) 219.1380, found 219.1368.
2-(Benzo[d][1,3]dioxol-5-yl)-4-methylpent-4-en-2-ol 9. The gen-
eral procedure above was followed using 1-(benzo[d][1,3]dioxol-5-yl)-
ethanone 8 (164.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and
tert-amyl alcohol (176.3 mg, 2.0 mmol). After being allowed to sit
overnight, the reaction mixture was purified by column chromatog-
raphy on silica gel (eluting with 5% EtOAc/hexanes) to afford the
product 9 as a liquid (211.4 mg, 96%): 1H NMR (400 MHz, CDCl3),
δ 6.95 (s, 1H), 6.90 (dd, 2H, J = 1.4, 7.9 Hz), 6.75 (d, 1H, J = 8.1 Hz),
5.94 (s, 2H), 4.90 (s, 1H), 4.73 (s, 1H), 2.59 (d, 1H, J = 13.3 Hz), 2.47
(d, 1H, J = 13.4 Hz), 2.29 (s, 1H), 1.52 (s, 3H), 1.45 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 147.5, 146.0, 142.5, 142.3, 117.9, 115.7,
107.7, 106.0, 100.9, 73.1, 52.1, 30.8, 24.2; HRMS (ES pos) m/z calcd
+
for C13H15O2 (M −H2O + H+) 203.1067, found 203.1056.
1-Bromo-2-(4-methoxyphenyl)-4-methylpent-4-en-2-ol 11. The
general procedure above was followed using 2-bromo-1-(4-
methoxyphenyl)ethanone 10 (229.1 mg, 1.0 mmol), 1 (1.5 mmol,
1.5 equiv), and tert-amyl alcohol (176.3 mg, 2.0 mmol). After being
allowed to sit overnight, the reaction mixture was purified by column
chromatography on silica gel (eluting with 5% EtOAc/hexanes) to
1
afford the product 11 as a liquid (282.3 mg, 99%): H NMR (400
MHz, CDCl3), δ 7.36−7.26 (m, 2H), 6.90−6.87 (m, 2H), 4.86 (bs,
1H), 4.71 (bs, 1H), 3.81 (s, 3H), 3.76 (s, 2H), 2.74 (d, 1H, J = 13.6
Hz), 2.65 (d, 1H, J = 13.8 Hz), 2.63 (s, 1H), 1.46 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 158.8, 141.5, 135.2, 126.7, 116.1, 113.6, 74.3,
55.2, 48.2, 45.3, 24.1; HRMS (ES pos) m/z calcd for (C13H16BrO)+
(M − H2O + H+) 267.0379, found 267.0380.
3-Hydroxy-3-(4-methoxyphenyl)-5-methylhex-5-enenitrile 13.
The general procedure above was followed, using 3-(4-methoxyphen-
yl)-3-oxopropanenitrile 12 (175.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5
equiv), and tert-amyl alcohol (176.3 mg, 2.0 mmol). After being
allowed to sit overnight, the reaction mixture was purified by column
chromatography on silica gel (eluting with 5% EtOAc/hexanes) to
tert-Butyl 4-(2-Hydroxy-4-methylpent-4-en-2-yl)phenyl Carbo-
nate 25. The general procedure above was followed using 4-
acetylphenyl tert-butyl carbonate 24 (236.3 mg, 1.0 mmol), 1 (1.5
mmol, 1.5 equiv), and tert-amyl alcohol (176.3 mg, 2.0 mmol). After
being allowed to sit overnight, the reaction mixture was purified by
column chromatography on silica gel (eluting with 5% EtOAc/
hexanes) to afford the product 25 as a solid (286.5 mg, 98%): mp 62−
64 °C; 1H NMR (400 MHz, CDCl3), δ 7.44 (d, 2H, J = 8.9 Hz), 7.12
1
afford the product 13 as a liquid (229.0 mg, 99%): H NMR (400
MHz, CDCl3), δ 7.38−7.36 (m, 2H), 6.91−6.89 (m, 2H), 4.97 (bs,
1H), 4.83 (bs, 1H), 3.81 (s, 3H), 2.83 (s, 2H), 2.78 (d, 1H, J = 13.5
Hz), 2.71 (d, 1H, J = 13.5 Hz), 2.68 (s, 1H), 1.39 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 159.2, 141.0, 135.4, 126.2, 117.3, 117.2, 113.9,
72.9, 55.3, 49.2, 32.9, 24.0; HRMS (ES pos) m/z calcd for
+
+
C14H21N2O2 (M + NH4 ) 249.1598, found 249.1588.
E
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
+
+
(d, 2H, J = 8.6 Hz), 4.90 (s, 1H), 4.74 (s, 1H), 2.62 (d, 1H, J = 13.4
Hz), 2.51 (d, 1H, J = 13.4 Hz), 2.30 (s, 2H), 1.55 (bs, 12H), 1.43
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 151.9, 149.7, 145.5, 142.4,
125.9, 120.7, 115.8, 83.4, 73.0, 51.9, 30.7, 27.7, 24.3. HRMS (ES pos)
HRMS (ES pos) m/z calcd for C19H26BO2 (M + NH4 ) 297.2020,
found 297.2013.
Ethyl 3-Hydroxy-3-(2-methoxyphenyl)-5-methylhex-5-enoate 37.
The general procedure above was followed, using ethyl 3-(2-
methoxyphenyl)-3-oxopropanoate 36 (222.2 mg, 1.0 mmol), 1 (1.5
mmol, 1.5 equiv), and tert-amyl alcohol (176.3 mg, 2.0 mmol). After
being allowed to sit overnight, the reaction mixture was purified by
column chromatography on silica gel (eluting with 5% EtOAc/
+
+
m/z calcd for C17H28NO4 (M + NH4 ) 310.2013, found 310.2010.
4-Methyl-2-(thiophene-2-yl)pent-4-en-2-ol 27.24 The general
procedure above was followed using 1-(thiophen-2-yl)ethanone 26
(126.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol
(176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 27 as a waxy
solid (167.7 mg, 92%): 1H NMR (400 MHz, CDCl3), δ 7.27 (m, 1H),
7.14 (m, 1H), 7.04 (m, 1H), 4.91 (s, 1H), 4.75 (s, 1H), 2.59 (d, 1H,
J = 13.3 Hz), 2.50 (dd, 1H, J = 0.8, 13.2 Hz), 1.56 (bs, 12H), 1.45
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 150.1, 142.5, 125.8, 119.3,
115.6, 72.4, 51.8, 30.2, 24.0; HRMS (ES pos) m/z calcd for C10H13S+
1
hexanes) to afford the product 37 as a liquid (258.9 mg, 93%): H
NMR (400 MHz, CDCl3), δ 7.57−7.60 (m, 1H),7.19−7.25 (m, 1H),
6.94 (t, 1H, J = 7.6 Hz), 6.84 (d, 1H, J = 8.1 Hz), 4.74 (s, 1H), 4.62
(s, 1H), 4.35 (s, 1H), 3.95 (q, 2H, J = 7.0 Hz), 3.85 (s, 3H), 3.33 (d,
1H, J = 15.1 Hz), 2.79−2.86 (m, 2H), 2.62 (d, 1H, J = 13.3 Hz), 1.56
(s, 3H), 1.03 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3) δ
173.2, 155.7, 142.7, 132.6, 128.4, 127.7. 127.6, 120.5, 114.6, 110.8,
74.7, 60.3, 55.1, 47.3, 43.6, 24.1, 13.9; HRMS (ES pos) m/z calcd for
+
+
+
C18H29N2O4 (M + CH3CN + NH4 ) 337.2122, found 337.2110.
2-(2-Methylallyl)-1,2,3,4-tetrahydronaphthalene-2,6-diol 39. To
a dry vial were charged 6-hydroxy-3,4-dihydronaphthalen-2(1H)-one
38 (162.2 mg, 1.0 mmol) and 1 (1.5 mmol, 1.5 equiv) under nitrogen.
After being allowed to sit overnight, the reaction mixture was purified
by column chromatography on silica gel (eluting with 5% EtOAc/
hexanes) to afford the product 39 as a solid (179.0 mg, 82%): mp
110−111 °C; 1H NMR (400 MHz, DMSO-d6), δ 9.0 (s, 1H), 6.78 (dd,
1H, J = 8 Hz), 6.51−6.47 (m, 2H), 4.83 (s, 1H), 4.64 (s, 1H), 4.24
(s, 1H), 2.80−2.78 (m, 1H), 2.64−2.50 (m, 3H), 1.84 (s, 3H), 1.72−1.57
(m, 2H);13C NMR (100 MHz, DMSO-d6) δ 154.8, 143.0, 136.4, 130.0,
125.6, 114.4, 113.8, 113.0, 69.7, 48.8, 40.7, 33.7, 26.1, 24.7; HRMS (ES
pos) m/z calcd for C14H22NO2+ (M + NH4+) 236.1645, found 236.1639.
Procedure for Synthesis of 1,2-Bis(4-methoxyphenyl)-4-
methylpent-4-ene-1,2-diol 33 on 10 g Scale. To a dry flask
were charged 2-hydroxy-1,2-bis(4-methoxyphenyl)ethanone 32 (10.0
g, 36.7 mmol), 1 (55.1 mmol, 1.5 equiv), and tert-amyl alcohol (6.47 g,
73.45 mmol, 2.0 equiv) under nitrogen. The resulting solution was
then allowed to stir at 35 °C overnight. After 20 mL of water was
added, the resulting mixture was stirred overnight. The solid was
collected and washed with water to give the analytically pure product
33 (9.7 g, 80% yield) as a white solid.
(M − H2O + NH4 ) 165.0732, found 165.0726.
2-(Benzofuran-3-yl)-4-methylpent-4-en-2-ol 29. The general
procedure above was followed using 1-(benzofuran-3-yl)ethanone 28
(160.2 mg, 1.0 mmol), 1 (1.5 mmol, 1.5 equiv), and tert-amyl alcohol
(176.3 mg, 2.0 mmol). After being allowed to sit overnight, the
reaction mixture was purified by column chromatography on silica gel
(eluting with 5% EtOAc/hexanes) to afford the product 29 as a solid
1
(212.0 mg, 98%): mp 37−38 °C; H NMR (400 MHz, CDCl3), δ
7.51−7.44 (m, 2H), 7.26−7.18 (m, 2H), 6.60 (s, 1H), 4.92 ((m, 1H),
4.91 (s, 1H), 4.75 (s, 1H), 2.81 (d, 1H, J = 13.2 Hz), 2.57 (dd, 1H, J =
0.72, 13.2 Hz), 1.56 (bs, 12H), 1.45 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 150.1, 142.5, 125.8, 119.3, 115.6, 72.4, 51.8, 30.2, 24.0; HRMS
(ES pos) m/z calcd for C14H15O+ (M − H2O + H+) 199.1117, found
199.1123.
(1S,2S,4R)-2-Hydroxy-7,7-dimethyl-2-(2-methylallyl)bicyclo-
[2.2.1]heptane-1-carboxylic Acid 31. To a dry vial was charged
(1S,4R)-7,7-dimethyl-2-oxobicyclo[2.2.1]heptane-1-carboxylic acid 30
(182.2 mg, 1.0 mmol) and 1 (1.5 mmol, 1.5 equiv) under nitrogen.
After being allowed to sit overnight, the reaction mixture was purified
by column chromatography on silica gel (eluting with 5% EtOAc/
hexanes) to afford the product 31 as a solid (212.1 mg, 89%): mp
1
132−134 °C; H NMR (400 MHz, CDCl3), δ 5.09 (s, 1H), 4.90
(s, 1H), 2.58−2.20 (m, 4H), 1.94−1.85 (m, 5H), 1.75−1.68 (m, 2H),
1.34 (s, 3H), 1.16−1.11 (m, 1H), 1.08 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 1757, 142.1. 117.8, 79.9, 62.6, 52.9, 47.9, 47.7, 46.6, 27.0, 26.7,
24.2, 22.0, 21.6; HRMS (ES pos) m/z calcd for C14H23O3+ (M + H+)
239.1642, found 239.1638.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR of all new compounds. This
material is available free of charge via the Internet at http://
pubs.acs.org.
1,2-Bis(4-methoxyphenyl)-4-methylpent-4-ene-1,2-diol 33. The
general procedure above was followed using 2-hydroxy-1,2-bis(4-
methoxyphenyl)ethanone 32 (272.3 mg, 1.0 mmol), 1 (1.5 mmol, 1.5
equiv), and t-amyl alcohol (176.3 mg, 2.0 mmol). After being allowed
to sit overnight, the reaction mixture was purified by column
chromatography on silica gel (eluting with 5% EtOAc/hexanes) to
afford the product 33 as a solid (279.1 mg, 85%): mp 136−137 °C; 1H
NMR (400 MHz, CDCl3), δ 7.06 (d, 2H, J = 8 Hz), 6.95 (d, 2H, J = 8
Hz), 6.73−6.68 (m, 4H), 4.75−4.71 (m, 2H), 3.76 (s, 3H), 3.75
(s, 3H), 2.90−2.69 (m, 4H), 1.34 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 158.9, 158.3, 142.4, 134.1, 131.8, 129.0, 127.7, 116.0, 112.8,
112.7, 80.6, 55.1, 46.1, 24.4. HRMS (ES pos) m/z calcd for C20H26NO3+
(M − H2O − NH4+) 328.1907, found 328.1894.
AUTHOR INFORMATION
Corresponding Author
*E-mail: yongda.zhang@boehringer-ingelheim.com.
Notes
■
The authors declare no competing financial interest.
REFERENCES
■
(1) Hatano, M.; Ishihara, K. Synthesis 2008, 11, 1647.
(2) Schneider, U.; Useno, M.; Kobayashi, S. J. Am. Chem. Soc. 2008,
130, 13824.
(3) Schneider, U.; Kobayashi, S. Angew. Chem., Int. Ed. 2007, 46,
5909.
(4) Nowrouzi, F.; Janetzko, J.; Batey, R. A. Org. Lett. 2010, 12, 5490.
(5) Shibasaki, M.; Kanai, M. Chem Rev 2008, 108, 2853.
(6) Baker, T. J.; Jarvo, E. R. Org. Lett. 2009, 11, 1047.
(7) Fandrick, K. R.; Fandrick, D. R.; Gao, J. J.; Reeves, J. T.; Tan, Z.;
Li, W.; Song, J. J.; Lu, B.; Yee, N. K.; Senanayake, C. H. Org. Lett.
2010, 12, 3748.
1-(2-Methylallyl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
2,3-dihydro-1H-inden-1-ol 35. The general procedure above was
followed using 6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-di-
hydro-1H-inden-1-one 34 (258.1 mg, 1.0 mmol), 1 (1.5 mmol, 1.5
equiv), and tert-amyl alcohol (176.3 mg, 2.0 mmol). After being
allowed to sit overnight, the reaction mixture was purified by column
chromatography on silica gel (eluting with 5% EtOAc/hexanes) to
1
afford the product 35 as a liquid (264.0 mg, 84%): H NMR (400
MHz, CDCl3), δ 7.8 (s, 1H), 7.71 (d, 1H, J = 7.5 Hz), 7.2 (d, 1H, J =
7.8 Hz), 4.92 (s, 1H), 4.80 (s, 1H), 2.96−3.06 (m, 1H), 2.77−2.86
(m, 2H), 2.34−2.45 (m, 2H), 2.02−2.12 (m, 2H), 1.75 (s, 3H), 1.34
(s, 12H); 13C NMR (100 MHz, CDCl3) δ 147.3, 146.6. 142.7, 134.9,
129.0, 124.4, 115.0, 83.7, 82.7, 48.1, 39.4, 29.8, 39.4, 29.9, 24.9, 24.8;
(8) Zhang, P.; Morken, J. P. J. Am. Chem. Soc. 2009, 131, 12550.
(9) During preparation of our manuscript, direct allylboration of
ketones with allylboronic acid in THF or CHCl3 was reported by
Szabo and co-workers. Raducan, M.; Alam, R.; Szabo, K. J. Angew.
́
́
Chem., Int. Ed. 2012, 51, 13050.
F
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(10) Direct allylboration of ketones with B-allyl-1,3,2-dioxaborinane
upon heating overnight was described by Schaus and co-workers;
however, no detailed information about the reaction rate and yields
was available. See: Barnett, D. S.; Moquist, P. N.; Schaus, S. E. Angew.
Chem., Int. Ed. 2009, 48, 1.
(11) Wang, Z.; Meng, X.-J.; Kabalka, G. W. Tetrahedron Lett. 1991,
32, 1945.
(12) The reaction with acetophenone and allyldiisopropoxyborate in
toluene at 0 °C gave 13% yield after 15 h. See: Lou, S.; Moquist, P. N.;
Schaus, S. E. J. Am. Chem. Soc. 2006, 128, 12660.
(13) Nowrouzi, F.; Thadani, A. N.; Batey, R. A. Org. Lett. 2009, 11,
2631.
(14) Matsuoka, H.; Kondo, K. Tetradedron Lett. 2009, 50, 2320.
(15) Reilly, M. K.; Rychnovsky, S. D. Org. Lett. 2010, 12, 4892.
(16) Zhang, Y.; Li, N.; Qu, B.; Ma, S.; Lee, H.; Gonnella, N. C.; Gao,
J.; Li, W.; Tan, Z.; Reeves, J. T.; Wang, J.; Lorenz, J. C.; Li, G.; Reeves,
D. C.; Pesmasiri, A.; Grinberg, N.; Haddad, N.; Lu, B. Z.; Song, J. J.;
Senanayake, C. H. Org. Lett. 2013, 15, 1710.
(17) See the definition of “solvent-free”: Walsh, P. J.; Li, H.; Parrodi,
C. A. d. Chem. Rev. 2007, 107, 2503.
(18) The B-methallyldioxaborinane 1 is stable for months at 23 °C
under nitrogen. It can be weighed in air. However, it is hygroscopic
and will decompose under air.
(19) Brown, H. C.; Racherla, U. S.; Pellechia, P. J. J. Org. Chem. 1990,
55, 1868.
(20) Gung, B. W.; Xue, X.; Roush, W. R. J. Am. Soc. Chem. 2002, 124,
10692.
(21) Mp of tert-amylOH: −12 °C. Mp of t-BuOH: 25 °C.
(22) Wang, Z.; Meng, X.-J.; Kabalka, G. W. Tetrahedron Lett. 1991,
32, 4619.
(23) Kim, J. G.; Camp, E. H.; Walsh, P. J. Org. Lett. 2006, 8, 4413.
(24) Imamoto, T.; Kusumoto, T.; Tawarayama, Y.; Sugiura, Y.; Mita,
T.; Hatanaka, Y.; YokoyamaJ, M. J. Org. Chem. 1984, 49, 3904.
G
dx.doi.org/10.1021/jo4006574 | J. Org. Chem. XXXX, XXX, XXX−XXX