59th Annual Report on Research 2014

My research group has benefited tremendously from the support of the ACS-PRF-UR grant. It has allowed me to fund three summer research students during the first year of the grant and purchase a variety of expendables that were needed for this project. Two of the students are currently beginning their senior year at ONU and both plan to attend graduate school in chemistry. Because of this support, my group recently published a paper and are now very close to another submission. An undergraduate research student and myself presented a poster at the fall ACS National meeting in San Francisco, CA (August 2014). Below is a summary of my group's progress over the past year (9/1/13 – 8/31/14).

My group spent the first half of this grant period working on a project that involved synthesizing a new class of dihydropyrazolopyrimidines. This class of compounds represents an important group of heterocycles due to their synthetic utility, significant biological activities and pharmacological importance as purine analogs.[1] Table 1 highlights a brief summary of this work, which was published in early 2014.[2]

Table 1. Radical and pyrazole scope of substituted dihydropyrazolo-pyrimidine formation.

Entry	Product	R1	R2	Yield (%)a
1	4a	iso-propyl	5-CH3	85
2	4b	tert-butyl	5-CH3	93
3	4c	c-hexyl	5-CH3	80
4	4d	c-pentyl	5-CH3	70
5	4e	ethyl	5-CH3	72
6	4f	iso-propyl	5-H	78
7	4g	iso-propyl	5-Ph	82
8	4h	iso-propyl	4-CN	85
9	4i	iso-propyl	4-CO2Et	70
10	4j	iso-propyl	4-Br-5-CH3	73

^a Isolated yields.

Currently my group is investigating the preparation of a new class of highly fluorescent chromone derivatives. We were interested in an inverse-demand hetero-Diels-Alder (IDHDA) reaction using silylenol ethers and 3-formylchromones. After studying this reaction for several months it was discovered that reacting enol ether 5 with a variety of formylchromones yielded conjugated enol products 6 (see Table 2). Furthermore, we found that simple irraditation of these compounds using a basic long-wave UV lamp (~365 nm) resulted blue fluorescence. There are a variety of commercially available 3-formylchromones and, therefore, we synthesized a small library of these enol products in order to study their fluorescent properties.

Table 2. Synthesis of fluorescent enol chromone derivatives.

Entry	R	Product	Yield (%)a
1	6-H	6a	77
2	6-CH3	6b	62
3	6-OCH3	6c	62
4	6-CH2CH3	6d	91
5	6-F	6f	87
6	6-Cl	6g	66
7	6-Br	6h	63
8	6-Cl, 7-CH3	6i	77
9	6,8-Cl	6j	71
10	6,8-Br	6k	54

^aIsolated yields.

Next, we focused on synthesizing compounds 7 which were easily prepared by condensing a variety of sulfonamides with 3-formylchromones. These sulfonamide derived starting materials also underwent fast IDHDA reactions with silylenol ether 5 (see Table 3). The resulting enamine products 8 gave intense green fluorescence under long-wave UV irradiation (~365 nm).

Table 3. Synthesis of fluorescent enamine chromones derivatives.

Entry	R	Product	Yield (%)a
1	6-H	8a	78
2	6-CH3	8b	80
3a	6-H	8c	72b
4a	6-CH3	8d	52b
5	6-CH2CH3	8e	70
6	6-OCH3	8f	97
7	6-F	8g	90
8	6-Cl	8h	80
9	6-Br	8i	88
10	6,8-Cl	8j	73

^a Isolated yield. ^b p-methoxy substitution on sulfonamide aryl ring.

With a series of new fluorophore compounds in hand, absorption and emission maxima along with quantum yields were measured in methylene chloride (Table 4). The enol compounds (6) gave emission maxima from ~450-485 nm. The quantum yields for the enol derivatives were moderate ranging from 2-20%. The enamine products gave significantly better quantum yields, especially when an electron-donating group is located on the chromone aryl ring (see entries 6, 10, 11 and 14).

Table 4. Absorption, emission and quantum yields for newly synthesized fluorophores.

Entry	Product	λabsa nm	λemb nm	Stoke Shift	Φc (%)
1	6a	362	446	84	7
2	6c	383	482	99	20
3	6f	364	486	122	2
4	6l	371	451	80	3
5	8a	358	479	121	37
6	8b	367	492	125	60
7	8b	380	468	88	8d
8	8b	364	479	115	27e
9	8c	358	479	121	28
10	8d	367	492	125	67
11	8e	370	490	120	64
12	8e	369	496	127	16d
13	8e	364	481	117	30e
14	8f	390	529	139	62
15	8g	367	492	125	33
16	8h	367	483	116	39
17	8i	343	483	140	34
18	8j	355	486	131	14
19	8k	368	489	121	21

^a Absorption maximum. ^b Emission maximum. ^c Fluorescent quantum yield in CH₂Cl₂.

^d Fluorescent quantum yield in CH₃CN. ^e Fluorescent quantum yield in cyclohexane.

In conclusion, we will continue to investigate the synthesis of these new fluorescent chromones. There are several sites on the starting materials that can be varied in order to tune the spectroscopic properties of these products.

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[2]. Zimmerman, J.; Myers, B.; Bouhall, S.; McCarthy, A.; Johntony, O; Manpadi, M. Tetrahedron Lett. 2014, 55, 936-940.